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1.  Continuous Subcutaneous Insulin Infusion (CSII) Pumps for Type 1 and Type 2 Adult Diabetic Populations 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this analysis is to review the efficacy of continuous subcutaneous insulin infusion (CSII) pumps as compared to multiple daily injections (MDI) for the type 1 and type 2 adult diabetics.
Clinical Need and Target Population
Insulin therapy is an integral component of the treatment of many individuals with diabetes. Type 1, or juvenile-onset diabetes, is a life-long disorder that commonly manifests in children and adolescents, but onset can occur at any age. It represents about 10% of the total diabetes population and involves immune-mediated destruction of insulin producing cells in the pancreas. The loss of these cells results in a decrease in insulin production, which in turn necessitates exogenous insulin therapy.
Type 2, or ‘maturity-onset’ diabetes represents about 90% of the total diabetes population and is marked by a resistance to insulin or insufficient insulin secretion. The risk of developing type 2 diabetes increases with age, obesity, and lack of physical activity. The condition tends to develop gradually and may remain undiagnosed for many years. Approximately 30% of patients with type 2 diabetes eventually require insulin therapy.
CSII Pumps
In conventional therapy programs for diabetes, insulin is injected once or twice a day in some combination of short- and long-acting insulin preparations. Some patients require intensive therapy regimes known as multiple daily injection (MDI) programs, in which insulin is injected three or more times a day. It’s a time consuming process and usually requires an injection of slow acting basal insulin in the morning or evening and frequent doses of short-acting insulin prior to eating. The most common form of slower acting insulin used is neutral protamine gagedorn (NPH), which reaches peak activity 3 to 5 hours after injection. There are some concerns surrounding the use of NPH at night-time as, if injected immediately before bed, nocturnal hypoglycemia may occur. To combat nocturnal hypoglycemia and other issues related to absorption, alternative insulins have been developed, such as the slow-acting insulin glargine. Glargine has no peak action time and instead acts consistently over a twenty-four hour period, helping reduce the frequency of hypoglycemic episodes.
Alternatively, intensive therapy regimes can be administered by continuous insulin infusion (CSII) pumps. These devices attempt to closely mimic the behaviour of the pancreas, continuously providing a basal level insulin to the body with additional boluses at meal times. Modern CSII pumps are comprised of a small battery-driven pump that is designed to administer insulin subcutaneously through the abdominal wall via butterfly needle. The insulin dose is adjusted in response to measured capillary glucose values in a fashion similar to MDI and is thus often seen as a preferred method to multiple injection therapy. There are, however, still risks associated with the use of CSII pumps. Despite the increased use of CSII pumps, there is uncertainty around their effectiveness as compared to MDI for improving glycemic control.
Part A: Type 1 Diabetic Adults (≥19 years)
An evidence-based analysis on the efficacy of CSII pumps compared to MDI was carried out on both type 1 and type 2 adult diabetic populations.
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 1 diabetes?
Are CSII pumps more effective than MDI for improving additional outcomes related to diabetes such as quality of life (QoL)?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, EMBASE, CINAHL
Adults (≥ 19 years)
Type 1 diabetes
Study evaluates CSII vs. MDI
Published between January 1, 2002 – March 24, 2009
Patient currently on intensive insulin therapy
Exclusion Criteria
Studies with <20 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcomes of interest were glycosylated hemoglobin (HbA1c) levels, mean daily blood glucose, glucose variability, and frequency of hypoglycaemic events. Other outcomes of interest were insulin requirements, adverse events, and quality of life.
Search Strategy
The literature search strategy employed keywords and subject headings to capture the concepts of:
1) insulin pumps, and
2) type 1 diabetes.
The search was run on July 6, 2008 in the following databases: Ovid MEDLINE (1996 to June Week 4 2008), OVID MEDLINE In-Process and Other Non-Indexed Citations, EMBASE (1980 to 2008 Week 26), OVID CINAHL (1982 to June Week 4 2008) the Cochrane Library, and the Centre for Reviews and Dissemination/International Agency for Health Technology Assessment. A search update was run on March 24, 2009 and studies published prior to 2002 were also examined for inclusion into the review. Parallel search strategies were developed for the remaining databases. Search results were limited to human and English-language published between January 2002 and March 24, 2009. Abstracts were reviewed, and studies meeting the inclusion criteria outlined above were obtained. Reference lists were also checked for relevant studies.
Summary of Findings
The database search identified 519 relevant citations published between 1996 and March 24, 2009. Of the 519 abstracts reviewed, four RCTs and one abstract met the inclusion criteria outlined above. While efficacy outcomes were reported in each of the trials, a meta-analysis was not possible due to missing data around standard deviations of change values as well as missing data for the first period of the crossover arm of the trial. Meta-analysis was not possible on other outcomes (quality of life, insulin requirements, frequency of hypoglycemia) due to differences in reporting.
HbA1c
In studies where no baseline data was reported, the final values were used. Two studies (Hanaire-Broutin et al. 2000, Hoogma et al. 2005) reported a slight reduction in HbA1c of 0.35% and 0.22% respectively for CSII pumps in comparison to MDI. A slightly larger reduction in HbA1c of 0.84% was reported by DeVries et al.; however, this study was the only study to include patients with poor glycemic control marked by higher baseline HbA1c levels. One study (Bruttomesso et al. 2008) showed no difference between CSII pumps and MDI on Hba1c levels and was the only study using insulin glargine (consistent with results of parallel RCT in abstract by Bolli 2004). While there is statistically significant reduction in HbA1c in three of four trials, there is no evidence to suggest these results are clinically significant.
Mean Blood Glucose
Three of four studies reported a statistically significant reduction in the mean daily blood glucose for patients using CSII pump, though these results were not clinically significant. One study (DeVries et al. 2002) did not report study data on mean blood glucose but noted that the differences were not statistically significant. There is difficulty with interpreting study findings as blood glucose was measured differently across studies. Three of four studies used a glucose diary, while one study used a memory meter. In addition, frequency of self monitoring of blood glucose (SMBG) varied from four to nine times per day. Measurements used to determine differences in mean daily blood glucose between the CSII pump group and MDI group at clinic visits were collected at varying time points. Two studies use measurements from the last day prior to the final visit (Hoogma et al. 2005, DeVries et al. 2002), while one study used measurements taken during the last 30 days and another study used measurements taken during the 14 days prior to the final visit of each treatment period.
Glucose Variability
All four studies showed a statistically significant reduction in glucose variability for patients using CSII pumps compared to those using MDI, though one, Bruttomesso et al. 2008, only showed a significant reduction at the morning time point. Brutomesso et al. also used alternate measures of glucose variability and found that both the Lability index and mean amplitude of glycemic excursions (MAGE) were in concordance with the findings using the standard deviation (SD) values of mean blood glucose, but the average daily risk range (ADRR) showed no difference between the CSII pump and MDI groups.
Hypoglycemic Events
There is conflicting evidence concerning the efficacy of CSII pumps in decreasing both mild and severe hypoglycemic events. For mild hypoglycemic events, DeVries et al. observed a higher number of events per patient week in the CSII pump group than the MDI group, while Hoogma et al. observed a higher number of events per patient year in the MDI group. The remaining two studies found no differences between the two groups in the frequency of mild hypoglycemic events. For severe hypoglycemic events, Hoogma et al. found an increase in events per patient year among MDI patients, however, all of the other RCTs showed no difference between the patient groups in this aspect.
Insulin Requirements and Adverse Events
In all four studies, insulin requirements were significantly lower in patients receiving CSII pump treatment in comparison to MDI. This difference was statistically significant in all studies. Adverse events were reported in three studies. Devries et al. found no difference in ketoacidotic episodes between CSII pump and MDI users. Bruttomesso et al. reported no adverse events during the study. Hanaire-Broutin et al. found that 30 patients experienced 58 serious adverse events (SAEs) during MDI and 23 patients had 33 SAEs during treatment out of a total of 256 patients. Most events were related to severe hypoglycemia and diabetic ketoacidosis.
Quality of Life and Patient Preference
QoL was measured in three studies and patient preference was measured in one. All three studies found an improvement in QoL for CSII users compared to those using MDI, although various instruments were used among the studies and possible reporting bias was evident as non-positive outcomes were not consistently reported. Moreover, there was also conflicting results in two of the studies using the Diabetes Treatment Satisfaction Questionnaire (DTSQ). DeVries et al. reported no difference in treatment satisfaction between CSII pump users and MDI users while Brutomesso et al. reported that treatment satisfaction improved among CSII pump users.
Patient preference for CSII pumps was demonstrated in just one study (Hanaire-Broutin et al. 2000) and there are considerable limitations with interpreting this data as it was gathered through interview and 72% of patients that preferred CSII pumps were previously on CSII pump therapy prior to the study. As all studies were industry sponsored, findings on QoL and patient preference must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low due to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 1) While blinding of patient to intervention/control was not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. Trials reported consistent results for the outcomes HbA1c, mean blood glucose and glucose variability, but the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as most trials used highly motivated populations with fairly good glycemic control. In addition, the populations in each of the studies varied with respect to prior treatment regimens, which may not be generalizable to the population eligible for pumps in Ontario. For the outcome of hypoglycaemic events the evidence was further downgraded to very low since there was conflicting evidence between studies with respect to the frequency of mild and severe hypoglycaemic events in patients using CSII pumps as compared to CSII (see Table 2). The GRADE quality of evidence for the use of CSII in adults with type 1 diabetes is therefore low to very low and any estimate of effect is, therefore, uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c, Mean Blood Glucose, and Glucose Variability for Adults with Type 1 Diabetes
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
HbA1c: 3/4 studies show consistency however magnitude of effect varies greatly; Single study uses insulin glargine instead of NPH; Mean Blood Glucose: 3/4 studies show consistency however magnitude of effect varies between studies; Glucose Variability: All studies show consistency but 1 study only showed a significant effect in the morning
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
GRADE Quality Assessment for CSII pumps vs. MDI on Frequency of Hypoglycemic
Inadequate or unknown allocation concealment (3/4 studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; No ITT analysis (2/4 studies); possible bias SMBG (all studies)
Conflicting evidence with respect to mild and severe hypoglycemic events reported in studies
Generalizability in question due to varying populations: highly motivated populations, educational component of interventions/ run-in phases, insulin pen use in 2/4 studies and varying levels of baseline glycemic control and experience with intensified insulin therapy, pumps and MDI.
Economic Analysis
One article was included in the analysis from the economic literature scan. Four other economic evaluations were identified but did not meet our inclusion criteria. Two of these articles did not compare CSII with MDI and the other two articles used summary estimates from a mixed population with Type 1 and 2 diabetes in their economic microsimulation to estimate costs and effects over time. Included were English articles that conducted comparisons between CSII and MDI with the outcome of Quality Adjusted Life Years (QALY) in an adult population with type 1 diabetes.
From one study, a subset of the population with type 1 diabetes was identified that may be suitable and benefit from using insulin pumps. There is, however, limited data in the literature addressing the cost-effectiveness of insulin pumps versus MDI in type 1 diabetes. Longer term models are required to estimate the long term costs and effects of pumps compared to MDI in this population.
Conclusions
CSII pumps for the treatment of adults with type 1 diabetes
Based on low-quality evidence, CSII pumps confer a statistically significant but not clinically significant reduction in HbA1c and mean daily blood glucose as compared to MDI in adults with type 1 diabetes (>19 years).
CSII pumps also confer a statistically significant reduction in glucose variability as compared to MDI in adults with type 1 diabetes (>19 years) however the clinical significance is unknown.
There is indirect evidence that the use of newer long-acting insulins (e.g. insulin glargine) in MDI regimens result in less of a difference between MDI and CSII compared to differences between MDI and CSII in which older insulins are used.
There is conflicting evidence regarding both mild and severe hypoglycemic events in this population when using CSII pumps as compared to MDI. These findings are based on very low-quality evidence.
There is an improved quality of life for patients using CSII pumps as compared to MDI however, limitations exist with this evidence.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
All studies used crossover design
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations were highly motivated and half of studies used insulin pens as the mode of delivery for MDI
One short-term study concluded that pumps are cost-effective, although this was based on limited data and longer term models are required to estimate the long-term costs and effects of pumps compared to MDI in adults with type 1 diabetes.
Part B: Type 2 Diabetic Adults
Research Questions
Are CSII pumps more effective than MDI for improving glycemic control in adults (≥19 years) with type 2 diabetes?
Are CSII pumps more effective than MDI for improving other outcomes related to diabetes such as quality of life?
Literature Search
Inclusion Criteria
Randomized controlled trials, systematic reviews, meta-analysis and/or health technology assessments from MEDLINE, Excerpta Medica Database (EMBASE), Cumulative Index to Nursing & Allied Health Literature (CINAHL)
Any person with type 2 diabetes requiring insulin treatment intensive
Published between January 1, 2000 – August 2008
Exclusion Criteria
Studies with <10 patients
Studies <5 weeks in duration
CSII applied only at night time and not 24 hours/day
Mixed group of diabetes patients (children, adults, type 1, type 2)
Pregnancy studies
Outcomes of Interest
The primary outcome of interest was a reduction in glycosylated hemoglobin (HbA1c) levels. Other outcomes of interest were mean blood glucose level, glucose variability, insulin requirements, frequency of hypoglycemic events, adverse events, and quality of life.
Search Strategy
A comprehensive literature search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, CINAHL, The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and August 15, 2008. Studies meeting the inclusion criteria were selected from the search results. Data on the study characteristics, patient characteristics, primary and secondary treatment outcomes, and adverse events were abstracted. Reference lists of selected articles were also checked for relevant studies. The quality of the evidence was assessed as high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The database search identified 286 relevant citations published between 1996 and August 2008. Of the 286 abstracts reviewed, four RCTs met the inclusion criteria outlined above. Upon examination, two studies were subsequently excluded from the meta-analysis due to small sample size and missing data (Berthe et al.), as well as outlier status and high drop out rate (Wainstein et al) which is consistent with previously reported meta-analyses on this topic (Jeitler et al 2008, and Fatourechi M et al. 2009).
HbA1c
The primary outcome in this analysis was reduction in HbA1c. Both studies demonstrated that both CSII pumps and MDI reduce HbA1c, but neither treatment modality was found to be superior to the other. The results of a random effects model meta-analysis showed a mean difference in HbA1c of -0.14 (-0.40, 0.13) between the two groups, which was found not to be statistically or clinically significant. There was no statistical heterogeneity observed between the two studies (I2=0%).
Forrest plot of two parallel, RCTs comparing CSII to MDI in type 2 diabetes
Secondary Outcomes
Mean Blood Glucose and Glucose Variability
Mean blood glucose was only used as an efficacy outcome in one study (Raskin et al. 2003). The authors found that the only time point in which there were consistently lower blood glucose values for the CSII group compared to the MDI group was 90 minutes after breakfast. Glucose variability was not examined in either study and the authors reported no difference in weight gain between the CSII pump group and MDI groups at the end of study. Conflicting results were reported regarding injection site reactions between the two studies. Herman et al. reported no difference in the number of subjects experiencing site problems between the two groups, while Raskin et al. reported that there were no injection site reactions in the MDI group but 15 such episodes among 8 participants in the CSII pump group.
Frequency of Hypoglycemic Events and Insulin Requirements
All studies reported that there were no differences in the number of mild hypoglycemic events in patients on CSII pumps versus MDI. Herman et al. also reported no differences in the number of severe hypoglycemic events in patients using CSII pumps compared to those on MDI. Raskin et al. reported that there were no severe hypoglycemic events in either group throughout the study duration. Insulin requirements were only examined in Herman et al., who found that daily insulin requirements were equal between the CSII pump and MDI treatment groups.
Quality of Life
QoL was measured by Herman et al. using the Diabetes Quality of Life Clinical Trial Questionnaire (DQOLCTQ). There were no differences reported between CSII users and MDI users for treatment satisfaction, diabetes impact, and worry-related scores. Patient satisfaction was measured in Raskin et al. using a patient satisfaction questionnaire, whose results indicated that patients in the CSII pump group had significantly greater improvement in overall treatment satisfaction at the end of the study compared to the MDI group. Although patient preference was also reported, it was only examined in the CSII pump group, thus results indicating a greater preference for CSII pumps in this groups (as compared to prior injectable insulin regimens) are biased and must be interpreted with caution.
Quality of Evidence
Overall, the body of evidence was downgraded from high to low according to study quality and issues with directness as identified using the GRADE quality assessment tool (see Table 3). While blinding of patient to intervention/control is not feasible in these studies, blinding of study personnel during outcome assessment and allocation concealment were generally lacking. ITT was not clearly explained in one study and heterogeneity between study populations was evident from participants’ treatment regimens prior to study initiation. Although trials reported consistent results for HbA1c outcomes, the directness or generalizability of studies, particularly with respect to the generalizability of the diabetic population, was questionable as trials required patients to adhere to an intense SMBG regimen. This suggests that patients were highly motivated. In addition, since prior treatment regimens varied between participants (no requirement for patients to be on MDI), study findings may not be generalizable to the population eligible for a pump in Ontario. The GRADE quality of evidence for the use of CSII in adults with type 2 diabetes is, therefore, low and any estimate of effect is uncertain.
GRADE Quality Assessment for CSII pumps vs. MDI on HbA1c Adults with Type 2 Diabetes
Inadequate or unknown allocation concealment (all studies); Unblinded assessment (all studies) however lack of blinding due to the nature of the study; ITT not well explained in 1 of 2 studies
Indirect due to lack of generalizability of findings since participants varied with respect to prior treatment regimens and intensive SMBG suggests highly motivated populations used in trials.
Economic Analysis
An economic analysis of CSII pumps was carried out using the Ontario Diabetes Economic Model (ODEM) and has been previously described in the report entitled “Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario”, part of the diabetes strategy evidence series. Based on the analysis, CSII pumps are not cost-effective for adults with type 2 diabetes, either for the age 65+ sub-group or for all patients in general. Details of the analysis can be found in the full report.
Conclusions
CSII pumps for the treatment of adults with type 2 diabetes
There is low quality evidence demonstrating that the efficacy of CSII pumps is not superior to MDI for adult type 2 diabetics.
There were no differences in the number of mild and severe hypoglycemic events in patients on CSII pumps versus MDI.
There are conflicting findings with respect to an improved quality of life for patients using CSII pumps as compared to MDI.
Significant limitations of the literature exist specifically:
All studies sponsored by insulin pump manufacturers
Prior treatment regimens varied
Types of insulins used in study varied (NPH vs. glargine)
Generalizability of studies in question as populations may not reflect eligible patient population in Ontario (participants not necessarily on MDI prior to study initiation, pen used in one study and frequency of SMBG required during study was high suggesting highly motivated participants)
Based on ODEM, insulin pumps are not cost-effective for adults with type 2 diabetes either for the age 65+ sub-group or for all patients in general.
PMCID: PMC3377523  PMID: 23074525
2.  Meta-analyses of Adverse Effects Data Derived from Randomised Controlled Trials as Compared to Observational Studies: Methodological Overview 
PLoS Medicine  2011;8(5):e1001026.
Su Golder and colleagues carry out an overview of meta-analyses to assess whether estimates of the risk of harm outcomes differ between randomized trials and observational studies. They find that, on average, there is no difference in the estimates of risk between overviews of observational studies and overviews of randomized trials.
Background
There is considerable debate as to the relative merits of using randomised controlled trial (RCT) data as opposed to observational data in systematic reviews of adverse effects. This meta-analysis of meta-analyses aimed to assess the level of agreement or disagreement in the estimates of harm derived from meta-analysis of RCTs as compared to meta-analysis of observational studies.
Methods and Findings
Searches were carried out in ten databases in addition to reference checking, contacting experts, citation searches, and hand-searching key journals, conference proceedings, and Web sites. Studies were included where a pooled relative measure of an adverse effect (odds ratio or risk ratio) from RCTs could be directly compared, using the ratio of odds ratios, with the pooled estimate for the same adverse effect arising from observational studies. Nineteen studies, yielding 58 meta-analyses, were identified for inclusion. The pooled ratio of odds ratios of RCTs compared to observational studies was estimated to be 1.03 (95% confidence interval 0.93–1.15). There was less discrepancy with larger studies. The symmetric funnel plot suggests that there is no consistent difference between risk estimates from meta-analysis of RCT data and those from meta-analysis of observational studies. In almost all instances, the estimates of harm from meta-analyses of the different study designs had 95% confidence intervals that overlapped (54/58, 93%). In terms of statistical significance, in nearly two-thirds (37/58, 64%), the results agreed (both studies showing a significant increase or significant decrease or both showing no significant difference). In only one meta-analysis about one adverse effect was there opposing statistical significance.
Conclusions
Empirical evidence from this overview indicates that there is no difference on average in the risk estimate of adverse effects of an intervention derived from meta-analyses of RCTs and meta-analyses of observational studies. This suggests that systematic reviews of adverse effects should not be restricted to specific study types.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Whenever patients consult a doctor, they expect the treatments they receive to be effective and to have minimal adverse effects (side effects). To ensure that this is the case, all treatments now undergo exhaustive clinical research—carefully designed investigations that test new treatments and therapies in people. Clinical investigations fall into two main groups—randomized controlled trials (RCTs) and observational, or non-randomized, studies. In RCTs, groups of patients with a specific disease or condition are randomly assigned to receive the new treatment or a control treatment, and the outcomes (for example, improvements in health and the occurrence of specific adverse effects) of the two groups of patients are compared. Because the patients are randomly chosen, differences in outcomes between the two groups are likely to be treatment-related. In observational studies, patients who are receiving a specific treatment are enrolled and outcomes in this group are compared to those in a similar group of untreated patients. Because the patient groups are not randomly chosen, differences in outcomes between cases and controls may be the result of a hidden shared characteristic among the cases rather than treatment-related (so-called confounding variables).
Why Was This Study Done?
Although data from individual trials and studies are valuable, much more information about a potential new treatment can be obtained by systematically reviewing all the evidence and then doing a meta-analysis (so-called evidence-based medicine). A systematic review uses predefined criteria to identify all the research on a treatment; meta-analysis is a statistical method for combining the results of several studies to yield “pooled estimates” of the treatment effect (the efficacy of a treatment) and the risk of harm. Treatment effect estimates can differ between RCTs and observational studies, but what about adverse effect estimates? Can different study designs provide a consistent picture of the risk of harm, or are the results from different study designs so disparate that it would be meaningless to combine them in a single review? In this methodological overview, which comprises a systematic review and meta-analyses, the researchers assess the level of agreement in the estimates of harm derived from meta-analysis of RCTs with estimates derived from meta-analysis of observational studies.
What Did the Researchers Do and Find?
The researchers searched literature databases and reference lists, consulted experts, and hand-searched various other sources for studies in which the pooled estimate of an adverse effect from RCTs could be directly compared to the pooled estimate for the same adverse effect from observational studies. They identified 19 studies that together covered 58 separate adverse effects. In almost all instances, the estimates of harm obtained from meta-analyses of RCTs and observational studies had overlapping 95% confidence intervals. That is, in statistical terms, the estimates of harm were similar. Moreover, in nearly two-thirds of cases, there was agreement between RCTs and observational studies about whether a treatment caused a significant increase in adverse effects, a significant decrease, or no significant change (a significant change is one unlikely to have occurred by chance). Finally, the researchers used meta-analysis to calculate that the pooled ratio of the odds ratios (a statistical measurement of risk) of RCTs compared to observational studies was 1.03. This figure suggests that there was no consistent difference between risk estimates obtained from meta-analysis of RCT data and those obtained from meta-analysis of observational study data.
What Do These Findings Mean?
The findings of this methodological overview suggest that there is no difference on average in the risk estimate of an intervention's adverse effects obtained from meta-analyses of RCTs and from meta-analyses of observational studies. Although limited by some aspects of its design, this overview has several important implications for the conduct of systematic reviews of adverse effects. In particular, it suggests that, rather than limiting systematic reviews to certain study designs, it might be better to evaluate a broad range of studies. In this way, it might be possible to build a more complete, more generalizable picture of potential harms associated with an intervention, without any loss of validity, than by evaluating a single type of study. Such a picture, in combination with estimates of treatment effects also obtained from systematic reviews and meta-analyses, would help clinicians decide the best treatment for their patients.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001026.
The US National Institutes of Health provide information on clinical research; the UK National Health Service Choices Web site also has a page on clinical trials and medical research
The Cochrane Collaboration produces and disseminates systematic reviews of health-care interventions
Medline Plus provides links to further information about clinical trials (in English and Spanish)
doi:10.1371/journal.pmed.1001026
PMCID: PMC3086872  PMID: 21559325
3.  Water, Sanitation, Hygiene, and Soil-Transmitted Helminth Infection: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(3):e1001620.
In a systematic review and meta-analysis, Eric Strunz and colleagues examine whether improvements in water, sanitation, and hygiene (WASH) practices are associated with reduced risk of infections with soil-transmitted helminths.
Please see later in the article for the Editors' Summary
Background
Preventive chemotherapy represents a powerful but short-term control strategy for soil-transmitted helminthiasis. Since humans are often re-infected rapidly, long-term solutions require improvements in water, sanitation, and hygiene (WASH). The purpose of this study was to quantitatively summarize the relationship between WASH access or practices and soil-transmitted helminth (STH) infection.
Methods and Findings
We conducted a systematic review and meta-analysis to examine the associations of improved WASH on infection with STH (Ascaris lumbricoides, Trichuris trichiura, hookworm [Ancylostoma duodenale and Necator americanus], and Strongyloides stercoralis). PubMed, Embase, Web of Science, and LILACS were searched from inception to October 28, 2013 with no language restrictions. Studies were eligible for inclusion if they provided an estimate for the effect of WASH access or practices on STH infection. We assessed the quality of published studies with the Grades of Recommendation, Assessment, Development and Evaluation (GRADE) approach. A total of 94 studies met our eligibility criteria; five were randomized controlled trials, whilst most others were cross-sectional studies. We used random-effects meta-analyses and analyzed only adjusted estimates to help account for heterogeneity and potential confounding respectively.
Use of treated water was associated with lower odds of STH infection (odds ratio [OR] 0.46, 95% CI 0.36–0.60). Piped water access was associated with lower odds of A. lumbricoides (OR 0.40, 95% CI 0.39–0.41) and T. trichiura infection (OR 0.57, 95% CI 0.45–0.72), but not any STH infection (OR 0.93, 95% CI 0.28–3.11). Access to sanitation was associated with decreased likelihood of infection with any STH (OR 0.66, 95% CI 0.57–0.76), T. trichiura (OR 0.61, 95% CI 0.50–0.74), and A. lumbricoides (OR 0.62, 95% CI 0.44–0.88), but not with hookworm infection (OR 0.80, 95% CI 0.61–1.06). Wearing shoes was associated with reduced odds of hookworm infection (OR 0.29, 95% CI 0.18–0.47) and infection with any STH (OR 0.30, 95% CI 0.11–0.83). Handwashing, both before eating (OR 0.38, 95% CI 0.26–0.55) and after defecating (OR 0.45, 95% CI 0.35–0.58), was associated with lower odds of A. lumbricoides infection. Soap use or availability was significantly associated with lower infection with any STH (OR 0.53, 95% CI 0.29–0.98), as was handwashing after defecation (OR 0.47, 95% CI 0.24–0.90).
Observational evidence constituted the majority of included literature, which limits any attempt to make causal inferences. Due to underlying heterogeneity across observational studies, the meta-analysis results reflect an average of many potentially distinct effects, not an average of one specific exposure-outcome relationship.
Conclusions
WASH access and practices are generally associated with reduced odds of STH infection. Pooled estimates from all meta-analyses, except for two, indicated at least a 33% reduction in odds of infection associated with individual WASH practices or access. Although most WASH interventions for STH have focused on sanitation, access to water and hygiene also appear to significantly reduce odds of infection. Overall quality of evidence was low due to the preponderance of observational studies, though recent randomized controlled trials have further underscored the benefit of handwashing interventions. Limited use of the Joint Monitoring Program's standardized water and sanitation definitions in the literature restricted efforts to generalize across studies. While further research is warranted to determine the magnitude of benefit from WASH interventions for STH control, these results call for multi-sectoral, integrated intervention packages that are tailored to social-ecological contexts.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Worldwide, more than a billion people are infected with soil-transmitted helminths (STHs), parasitic worms that live in the human intestine (gut). These intestinal worms, including roundworm, hookworm, and whipworm, mainly occur in tropical and subtropical regions and are most common in developing countries, where personal hygiene is poor, there is insufficient access to clean water, and sanitation (disposal of human feces and urine) is inadequate or absent. STHs colonize the human intestine and their eggs are shed in feces and enter the soil. Humans ingest the eggs, either by touching contaminated ground or eating unwashed fruit and vegetables grown in such soil. Hookworm may enter the body by burrowing through the skin, most commonly when bare-footed individuals walk on infected soil. Repeated infection with STHs leads to a heavy parasite infestation of the gut, causing chronic diarrhea, intestinal bleeding, and abdominal pain. In addition the parasites compete with their human host for nutrients, leading to malnutrition, anemia, and, in heavily infected children, stunting of physical growth and slowing of mental development.
Why Was This Study Done?
While STH infections can be treated in the short-term with deworming medication, rapid re-infection is common, therefore a more comprehensive program of improved water, sanitation, and hygiene (WASH) is needed. WASH strategies include improvements in water access (e.g., water quality, water quantity, and distance to water), sanitation access (e.g., access to improved latrines, latrine maintenance, and fecal sludge management), and hygiene practices (e.g., handwashing before eating and/or after defecation, water treatment, soap use, wearing shoes, and water storage practices). WASH strategies have been shown to be effective for reducing rates of diarrhea and other neglected tropical diseases, such as trachoma; however, there is limited evidence linking specific WASH access or practices to STH infection rates. In this systematic review and meta-analysis, the researchers investigate whether WASH access or practices lower the risk of STH infections. A systematic review uses predefined criteria to identify all the research on a given topic; a meta-analysis is a statistical method that combines the results of several studies.
What Did the Researchers Do and Find?
The researchers identified 94 studies that included measurements of the relationship between WASH access and practices with one or more types of STHs. Meta-analyses of the data from 35 of these studies indicated that overall people with access to WASH strategies or practices were about half as likely to be infected with any STH. Specifically, a lower odds of infection with any STH was observed for those people who use treated water (odd ratio [OR] of 0.46), have access to sanitation (OR of 0.66), wear shoes (OR of 0.30), and use soap or have soap availability (OR of 0.53) compared to those without access to these practices or strategies. In addition, infection with roundworm was less than half as likely in those who practiced handwashing both before eating and after defecating than those who did not practice handwashing (OR of 0.38 and 0.45, respectively).
What Do These Findings Mean?
The studies included in this systematic review and meta-analysis have several shortcomings. For example, most were cross-sectional surveys—studies that examined the effect of WASH strategies on STH infections in a population at a single time point. Given this study design, people with access to WASH strategies may have shared other characteristics that were actually responsible for the observed reductions in the risk of STH infections. Consequently, the overall quality of the included studies was low and there was some evidence for publication bias (studies showing a positive association are more likely to be published than those that do not). Nevertheless, these findings confirm that WASH access and practices provide an effective control measure for STH. Controlling STHs in developing countries would have a huge positive impact on the physical and mental health of the population, especially children, therefore there should be more emphasis on expanding access to WASH as part of development guidelines and targets, in addition to short-term preventative chemotherapy currently used.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001620.
The US Centers for Disease Control and Prevention also provides detailed information on roundworm, whipworm, and hookworm infections
The World Health Organization provides information on soil-transmitted helminths, including a description of the current control strategy
Children Without Worms (CWW) partners with Johnson & Johnson, GlaxoSmithKline, the World Health Organization, national ministries of health and education, non-governmental organizations, and others to promote treatment and prevention of soil-transmitted helminthiasis. CWW advocates a four-pronged, comprehensive control strategy—Water, Sanitation, Hygiene Education, and Deworming (WASHED) to break the cycle of reinfection
The Global Network for Neglected Tropical Diseases, an advocacy initiative dedicated to raising the awareness, political will, and funding necessary to control and eliminate the most common neglected tropical diseases, provides information on infections with roundworm (ascariasis), whipworm (trichuriasis), and hookworm
WASH for the Neglected Tropical Diseases is a repository of information on WASH and the neglected tropical diseases (NTDs) such as soil-transmitted helminthiasis, and features a resource titled “WASH and the NTDs: A Manual for WASH Implementers.”
Two international programs promoting water sanitation are the World Health Organization Water Sanitation and Health program and the World Health Organization/United Nations Childrens Fund Joint Monitoring Programme for Water Supply and Sanitation
doi:10.1371/journal.pmed.1001620
PMCID: PMC3965411  PMID: 24667810
4.  Evidence for the Selective Reporting of Analyses and Discrepancies in Clinical Trials: A Systematic Review of Cohort Studies of Clinical Trials 
PLoS Medicine  2014;11(6):e1001666.
In a systematic review of cohort studies, Kerry Dwan and colleagues examine the evidence for selective reporting and discrepancies in analyses between journal publications and other documents for clinical trials.
Please see later in the article for the Editors' Summary
Background
Most publications about selective reporting in clinical trials have focussed on outcomes. However, selective reporting of analyses for a given outcome may also affect the validity of findings. If analyses are selected on the basis of the results, reporting bias may occur. The aims of this study were to review and summarise the evidence from empirical cohort studies that assessed discrepant or selective reporting of analyses in randomised controlled trials (RCTs).
Methods and Findings
A systematic review was conducted and included cohort studies that assessed any aspect of the reporting of analyses of RCTs by comparing different trial documents, e.g., protocol compared to trial report, or different sections within a trial publication. The Cochrane Methodology Register, Medline (Ovid), PsycInfo (Ovid), and PubMed were searched on 5 February 2014. Two authors independently selected studies, performed data extraction, and assessed the methodological quality of the eligible studies. Twenty-two studies (containing 3,140 RCTs) published between 2000 and 2013 were included. Twenty-two studies reported on discrepancies between information given in different sources. Discrepancies were found in statistical analyses (eight studies), composite outcomes (one study), the handling of missing data (three studies), unadjusted versus adjusted analyses (three studies), handling of continuous data (three studies), and subgroup analyses (12 studies). Discrepancy rates varied, ranging from 7% (3/42) to 88% (7/8) in statistical analyses, 46% (36/79) to 82% (23/28) in adjusted versus unadjusted analyses, and 61% (11/18) to 100% (25/25) in subgroup analyses. This review is limited in that none of the included studies investigated the evidence for bias resulting from selective reporting of analyses. It was not possible to combine studies to provide overall summary estimates, and so the results of studies are discussed narratively.
Conclusions
Discrepancies in analyses between publications and other study documentation were common, but reasons for these discrepancies were not discussed in the trial reports. To ensure transparency, protocols and statistical analysis plans need to be published, and investigators should adhere to these or explain discrepancies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
In the past, clinicians relied on their own experience when choosing the best treatment for their patients. Nowadays, they turn to evidence-based medicine—the systematic review and appraisal of trials, studies that investigate the benefits and harms of medical treatments in patients. However, evidence-based medicine can guide clinicians only if all the results from clinical trials are published in an unbiased and timely manner. Unfortunately, the results of trials in which a new drug performs better than existing drugs are more likely to be published than those in which the new drug performs badly or has unwanted side effects (publication bias). Moreover, trial outcomes that support the use of a new treatment are more likely to be published than those that do not support its use (outcome reporting bias). Recent initiatives—such as making registration of clinical trials in a trial registry (for example, ClinicalTrials.gov) a prerequisite for publication in medical journals—aim to prevent these biases, which pose a threat to informed medical decision-making.
Why Was This Study Done?
Selective reporting of analyses of outcomes may also affect the validity of clinical trial findings. Sometimes, for example, a trial publication will include a per protocol analysis (which considers only the outcomes of patients who received their assigned treatment) rather than a pre-planned intention-to-treat analysis (which considers the outcomes of all the patients regardless of whether they received their assigned treatment). If the decision to publish the per protocol analysis is based on the results of this analysis being more favorable than those of the intention-to-treat analysis (which more closely resembles “real” life), then “analysis reporting bias” has occurred. In this systematic review, the researchers investigate the selective reporting of analyses and discrepancies in randomized controlled trials (RCTs) by reviewing published studies that assessed selective reporting of analyses in groups (cohorts) of RCTs and discrepancies in analyses of RCTs between different sources (for example, between the protocol in a trial registry and the journal publication) or different sections of a source. A systematic review uses predefined criteria to identify all the research on a given topic.
What Did the Researchers Do and Find?
The researchers identified 22 cohort studies (containing 3,140 RCTs) that were eligible for inclusion in their systematic review. All of these studies reported on discrepancies between the information provided by the RCTs in different places, but none investigated the evidence for analysis reporting bias. Several of the cohort studies reported, for example, that there were discrepancies in the statistical analyses included in the different documents associated with the RCTs included in their analysis. Other types of discrepancies reported by the cohort studies included discrepancies in the reporting of composite outcomes (an outcome in which multiple end points are combined) and in the reporting of subgroup analyses (investigations of outcomes in subgroups of patients that should be predefined in the trial protocol to avoid bias). Discrepancy rates varied among the RCTs according to the types of analyses and cohort studies considered. Thus, whereas in one cohort study discrepancies were present in the statistical test used for the analysis of the primary outcome in only 7% of the included studies, they were present in the subgroup analyses of all the included studies.
What Do These Findings Mean?
These findings indicate that discrepancies in analyses between publications and other study documents such as protocols in trial registries are common. The reasons for these discrepancies in analyses were not discussed in trial reports but may be the result of reporting bias, errors, or legitimate departures from a pre-specified protocol. For example, a statistical analysis that is not specified in the trial protocol may sometimes appear in a publication because the journal requested its inclusion as a condition of publication. The researchers suggest that it may be impossible for systematic reviewers to distinguish between these possibilities simply by looking at the source documentation. Instead, they suggest, it may be necessary for reviewers to contact the trial authors. However, to make selective reporting of analyses more easily detectable, they suggest that protocols and analysis plans should be published and that investigators should be required to stick to these plans or explain any discrepancies when they publish their trial results. Together with other initiatives, this approach should help improve the quality of evidence-based medicine and, as a result, the treatment of patients.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001666.
Wikipedia has pages on evidence-based medicine, on systematic reviews, and on publication bias (note: Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
ClinicalTrials.gov provides information about the US National Institutes of Health clinical trial registry, including background information about clinical trials
The Cochrane Collaboration is a global independent network of health practitioners, researchers, patient advocates, and others that aims to promote evidence-informed health decision-making by producing high-quality, relevant, accessible systematic reviews and other synthesized research evidence; the Cochrane Handbook for Systematic Reviews of Interventions describes the preparation of systematic reviews in detail
PLOS Medicine recently launched a Reporting Guidelines Collection, an open-access collection of reporting guidelines, commentary, and related research on guidelines from across PLOS journals that aims to help advance the efficiency, effectiveness, and equitability of the dissemination of biomedical information
doi:10.1371/journal.pmed.1001666
PMCID: PMC4068996  PMID: 24959719
5.  Towards evidence based medicine for paediatricians 
In order to give the best care to patients and families, paediatricians need to integrate the highest quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence based” answers to common questions which are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format which has been successfully developed by Kevin Macaway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, through they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor search the grey, unpublished literature. What Archimedes offers are practical, best evidence based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching,2 and gaining answers.3) A brief report of the search used follows—this has been performed in a hierarchical way, to search for the best quality evidence to answer the question.4 A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal, and the measures of effect (such as number needed to treat, NNT) books by Sackett5 and Moyer6 may help. To pull the information together, a commentary is provided. But to make it all much more accessible, a box provides the clinical bottom lines.
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at www.bestbets.org. If your question still hasn't been answered, feel free to submit your summary according to the Instructions for Authors at www.archdischild.com. Three topics are covered in this issue of the journal:
Does neonatal BCG vaccination protect against tuberculous meningitis?
Does dexamethasone reduce the risk of extubation failure in ventilated children?
Should metformin be prescribed to overweight adolescents in whom dietary/behavioural modifications have not helped?
REFERENCES
1. Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
2. Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3. Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4. http://cebm.jr2.ox.ac.uk/docs/levels.htm (accessed July 2002).
5. Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
6. Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health, Issue 1. London: BMJ Books, 2000.
How to read your journals
Most people have their journals land, monthly, weekly, or quarterly, on their desk, courtesy of their professional associations. Then they sit, gathering dust and guilt, for a period of time. When the layer of either is too great for comfort (or the desk space is needed for some proper work), the wrapper is removed and the journal scanned. But does how people read reflect their information needs or their entertainment requirements?
It is not uncommon to find people straying from the editorial introduction to the value added sections (like obituaries, Lucina‐like summary pages, and end‐of‐article fillers) rather than face the impenetrable science that sits between them. I think that this is probably unhelpful, and would urge readers to do one more thing before placing the journal in the recycling. Scan the table of contents; if it mentions a systematic review or a randomised trial, then read at least the title and the abstract's conclusions. If you agree, pat yourself warmly on the back for being evidence based and up‐to‐date. If you disagree, ask if it will make any impact on your clinical (or personal) life. If it might, run through the methods and quickly appraise them. Does it supply higher quality evidence than that you already possess? If it does, it's worth reading. If it doesn't, don't bother too much.
There are new innovations which might aid the tedious task of consuming research effort. The on‐line Précis section of the Archives provides a highly readable version of the contents page to whet one's appetite. Finally, it's worth mentioning that evidence based summary materials (like Archimedes, or Journal Watch) are always worth reading—and if you didn't think that you wouldn't be here, would you?
PMCID: PMC2082933
Archimedes; evidence based medicine
6.  Behavioural Interventions for Type 2 Diabetes 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this report is to determine whether behavioural interventions1 are effective in improving glycemic control in adults with type 2 diabetes.
Background
Diabetes is a serious chronic condition affecting millions of people worldwide and is the sixth leading cause of death in Canada. In 2005, an estimated 8.8% of Ontario’s population had diabetes, representing more than 816,000 Ontarians. The direct health care cost of diabetes was $1.76 billion in the year 2000 and is projected to rise to a total cost of $3.14 billion by 2016. Much of this cost arises from the serious long-term complications associated with the disease including: coronary heart disease, stroke, adult blindness, limb amputations and kidney disease.
Type 2 diabetes accounts for 90–95% of diabetes and while type 2 diabetes is more prevalent in people aged 40 years and older, prevalence in younger populations is increasing due to a rise in obesity and physical inactivity in children.
Data from the United Kingdom Prospective Diabetes Study (UKPDS) has shown that tight glycemic control can significantly reduce the risk of developing serious complications in type 2 diabetics. Despite physicians’ and patients’ knowledge of the importance of glycemic control, Canadian data has shown that only 38% of patients with diabetes have HbA1C levels in the optimal range of 7% or less. This statistic highlights the complexities involved in the management of diabetes, which is characterized by extensive patient involvement in addition to the support provided by physicians. An enormous demand is, therefore, placed on patients to self-manage the physical, emotional and psychological aspects of living with a chronic illness.
Despite differences in individual needs to cope with diabetes, there is general agreement for the necessity of supportive programs for patient self-management. While traditional programs were didactic models with the goal of improving patients’ knowledge of their disease, current models focus on behavioural approaches aimed at providing patients with the skills and strategies required to promote and change their behaviour.
Several meta-analyses and systematic reviews have demonstrated improved health outcomes with self-management support programs in type 2 diabetics. They have all, however, either looked at a specific component of self-management support programs (i.e. self-management education) or have been conducted in specific populations. Most reviews are also qualitative and do not clearly define the interventions of interest, making findings difficult to interpret. Moreover, heterogeneity in the interventions has led to conflicting evidence on the components of effective programs. There is thus much uncertainty regarding the optimal design and delivery of these programs by policymakers.
Evidence-Based Analysis of Effectiveness
Research Questions
Are behavioural interventions effective in improving glycemic control in adults with type 2 diabetes?
Is the effectiveness of the intervention impacted by intervention characteristics (e.g. delivery of intervention, length of intervention, mode of instruction, interventionist etc.)?
Inclusion Criteria
English Language
Published between January 1996 to August 2008
Type 2 diabetic adult population (>18 years)
Randomized controlled trials (RCTs)
Systematic reviews, or meta-analyses
Describing a multi-faceted self-management support intervention as defined by the 2007 Self-Management Mapping Guide (1)
Reporting outcomes of glycemic control (HbA1c) with extractable data
Studies with a minimum of 6-month follow up
Exclusion Criteria
Studies with a control group other than usual care
Studies with a sample size <30
Studies without a clearly defined intervention
Outcomes of Interest
Primary outcome: glycemic control (HbA1c)
Secondary outcomes: systolic blood pressure (SBP) control, lipid control, change in smoking status, weight change, quality of life, knowledge, self-efficacy, managing psychosocial aspects of diabetes, assessing dissatisfaction and readiness to change, and setting and achieving diabetes goals.
Search Strategy
A search was performed in OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), The Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1996 and August 2008. Abstracts were reviewed by a single author and studies meeting the inclusion criteria outlined above were obtained. Data on population characteristics, glycemic control outcomes, and study design were extracted. Reference lists were also checked for relevant studies. The quality of the evidence was assessed as being either high, moderate, low, or very low according to the GRADE methodology.
Summary of Findings
The search identified 638 citations published between 1996 and August 2008, of which 12 met the inclusion criteria and one was a meta-analysis (Gary et al. 2003). The remaining 11 studies were RCTs (9 were used in the meta-analysis) and only one was defined as small (total sample size N=47).
Summary of Participant Demographics across studies
A total of 2,549 participants were included in the 11 identified studies. The mean age of participants reported was approximately 58 years and the mean duration of diabetes was approximately 6 years. Most studies reported gender with a mean percentage of females of approximately 67%. Of the eleven studies, two focused only on women and four included only Hispanic individuals. All studies evaluated type 2 diabetes patients exclusively.
Study Characteristics
The studies were conducted between 2002 and 2008. Approximately six of 11 studies were carried out within the USA, with the remaining studies conducted in the UK, Sweden, and Israel (sample size ranged from 47 to 824 participants). The quality of the studies ranged from moderate to low with four of the studies being of moderate quality and the remaining seven of low quality (based on the Consort Checklist). Differences in quality were mainly due to methodological issues such as inadequate description of randomization, sample size calculation allocation concealment, blinding and uncertainty of the use of intention-to-treat (ITT) analysis. Patients were recruited from several settings: six studies from primary or general medical practices, three studies from the community (e.g. via advertisements), and two from outpatient diabetes clinics. A usual care control group was reported in nine of 11 of the studies and two studies reported some type of minimal diabetes care in addition to usual care for the control group.
Intervention Characteristics
All of the interventions examined in the studies were mapped to the 2007 Self-management Mapping Guide. The interventions most often focused on problem solving, goal setting and encouraging participants to engage in activities that protect and promote health (e.g. modifying behaviour, change in diet, and increase physical activity). All of the studies examined comprehensive interventions targeted at least two self-care topics (e.g. diet, physical activity, blood glucose monitoring, foot care, etc.). Despite the homogeneity in the aims of the interventions, there was substantial clinical heterogeneity in other intervention characteristics such as duration, intensity, setting, mode of delivery (group vs. individual), interventionist, and outcomes of interest (discussed below).
Duration, Intensity and Mode of Delivery
Intervention durations ranged from 2 days to 1 year, with many falling into the range of 6 to 10 weeks. The rest of the interventions fell into categories of ≤ 2 weeks (2 studies), 6 months (2 studies), or 1 year (3 studies). Intensity of the interventions varied widely from 6 hours over 2 days, to 52 hours over 1 year; however, the majority consisted of interventions of 6 to 15 hours. Both individual and group sessions were used to deliver interventions. Group counselling was used in five studies as a mode of instruction, three studies used both individual and group sessions, and one study used individual sessions as its sole mode of instruction. Three studies also incorporated the use of telephone support as part of the intervention.
Interventionists and Setting
The following interventionists were reported (highest to lowest percentage, categories not mutually exclusive): nurse (36%), dietician (18%), physician (9%), pharmacist (9%), peer leader/community worker (18%), and other (36%). The ‘other’ category included interventionists such as consultants and facilitators with unspecified professional backgrounds. The setting of most interventions was community-based (seven studies), followed by primary care practices (three studies). One study described an intervention conducted in a pharmacy setting.
Outcomes
Duration of follow up of the studies ranged from 6 months to 8 years with a median follow-up duration of 12 months. Nine studies followed up patients at a minimum of two time points. Despite clear reporting of outcomes at follow up time points, there was poor reporting on whether the follow up was measured from participant entry into study or from end of intervention. All studies reported measures of glycemic control, specifically HbA1c levels. BMI was measured in five studies, while body weight was reported in two studies. Cholesterol was examined in three studies and blood pressure reduction in two. Smoking status was only examined in one of the studies. Additional outcomes examined in the trials included patient satisfaction, quality of life, diabetes knowledge, diabetes medication reduction, and behaviour modification (i.e. daily consumption of fruits/vegetables, exercise etc). Meta-analysis of the studies identified a moderate but significant reduction in HbA1c levels -0.44% 95%CI: -0.60, -0.29) for behavioural interventions in comparison to usual care for adults with type 2 diabetes. Subgroup analyses suggested the largest effects in interventions which were of at least duration and interventions in diabetics with higher baseline HbA1c (≥9.0). The quality of the evidence according to GRADE for the overall estimate was moderate and the quality of evidence for the subgroup analyses was identified as low.
Summary of Meta-Analysis of Studies Investigating the Effectiveness of Behavioural Interventions on HbA1c in Patients with Type 2 Diabetes.
Based on one study
Conclusions
Based on moderate quality evidence, behavioural interventions as defined by the 2007 Self-management mapping guide (Government of Victoria, Australia) produce a moderate reduction in HbA1c levels in patients with type 2 diabetes compared with usual care.
Based on low quality evidence, the interventions with the largest effects are those:
- in diabetics with higher baseline HbA1c (≥9.0)
- in which the interventions were of at least 1 year in duration
PMCID: PMC3377516  PMID: 23074526
7.  Epidemiology and Reporting Characteristics of Systematic Reviews 
PLoS Medicine  2007;4(3):e78.
Background
Systematic reviews (SRs) have become increasingly popular to a wide range of stakeholders. We set out to capture a representative cross-sectional sample of published SRs and examine them in terms of a broad range of epidemiological, descriptive, and reporting characteristics, including emerging aspects not previously examined.
Methods and Findings
We searched Medline for SRs indexed during November 2004 and written in English. Citations were screened and those meeting our inclusion criteria were retained. Data were collected using a 51-item data collection form designed to assess the epidemiological and reporting details and the bias-related aspects of the reviews. The data were analyzed descriptively. In total 300 SRs were identified, suggesting a current annual publication rate of about 2,500, involving more than 33,700 separate studies including one-third of a million participants. The majority (272 [90.7%]) of SRs were reported in specialty journals. Most reviews (213 [71.0%]) were categorized as therapeutic, and included a median of 16 studies involving 1,112 participants. Funding sources were not reported in more than one-third (122 [40.7%]) of the reviews. Reviews typically searched a median of three electronic databases and two other sources, although only about two-thirds (208 [69.3%]) of them reported the years searched. Most (197/295 [66.8%]) reviews reported information about quality assessment, while few (68/294 [23.1%]) reported assessing for publication bias. A little over half (161/300 [53.7%]) of the SRs reported combining their results statistically, of which most (147/161 [91.3%]) assessed for consistency across studies. Few (53 [17.7%]) SRs reported being updates of previously completed reviews. No review had a registration number. Only half (150 [50.0%]) of the reviews used the term “systematic review” or “meta-analysis” in the title or abstract. There were large differences between Cochrane reviews and non-Cochrane reviews in the quality of reporting several characteristics.
Conclusions
SRs are now produced in large numbers, and our data suggest that the quality of their reporting is inconsistent. This situation might be improved if more widely agreed upon evidence-based reporting guidelines were endorsed and adhered to by authors and journals. These results substantiate the view that readers should not accept SRs uncritically.
Data were collected on the epidemiological, descriptive, and reporting characteristics of recent systematic reviews. A descriptive analysis found inconsistencies in the quality of reporting.
Editors' Summary
Background.
In health care it is important to assess all the evidence available about what causes a disease or the best way to prevent, diagnose, or treat it. Decisions should not be made simply on the basis of—for example—the latest or biggest research study, but after a full consideration of the findings from all the research of good quality that has so far been conducted on the issue in question. This approach is known as “evidence-based medicine” (EBM). A report that is based on a search for studies addressing a clearly defined question, a quality assessment of the studies found, and a synthesis of the research findings, is known as a systematic review (SR). Conducting an SR is itself regarded as a research project and the methods involved can be quite complex. In particular, as with other forms of research, it is important to do everything possible to reduce bias. The leading role in developing the SR concept and the methods that should be used has been played by an international network called the Cochrane Collaboration (see “Additional Information” below), which was launched in 1992. However, SRs are now becoming commonplace. Many articles published in journals and elsewhere are described as being systematic reviews.
Why Was This Study Done?
Since systematic reviews are claimed to be the best source of evidence, it is important that they should be well conducted and that bias should not have influenced the conclusions drawn in the review. Just because the authors of a paper that discusses evidence on a particular topic claim that they have done their review “systematically,” it does not guarantee that their methods have been sound and that their report is of good quality. However, if they have reported details of their methods, then it can help users of the review decide whether they are looking at a review with conclusions they can rely on. The authors of this PLoS Medicine article wanted to find out how many SRs are now being published, where they are being published, and what questions they are addressing. They also wanted to see how well the methods of SRs are being reported.
What Did the Researchers Do and Find?
They picked one month and looked for all the SRs added to the main list of medical literature in that month. They found 300, on a range of topics and in a variety of medical journals. They estimate that about 20% of reviews appearing each year are published by the Cochrane Collaboration. They found many cases in which important aspects of the methods used were not reported. For example, about a third of the SRs did not report how (if at all) the quality of the studies found in the search had been assessed. An important assessment, which analyzes for “publication bias,” was reported as having been done in only about a quarter of the cases. Most of the reporting failures were in the “non-Cochrane” reviews.
What Do These Findings Mean?
The authors concluded that the standards of reporting of SRs vary widely and that readers should, therefore, not accept the conclusions of SRs uncritically. To improve this situation, they urge that guidelines be drawn up regarding how SRs are reported. The writers of SRs and also the journals that publish them should follow these guidelines.
Additional Information.
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.0040078.
An editorial discussing this research article and its relevance to medical publishing appears in the same issue of PLoS Medicine
A good source of information on the evidence-based approach to medicine is the James Lind Library
The Web site of the Cochrane Collaboration is a good source of information on systematic reviews. In particular there is a newcomers' guide and information for health care “consumers”. From this Web site, it is also possible to see summaries of the SRs published by the Cochrane Collaboration (readers in some countries can also view the complete SRs free of charge)
Information on the practice of evidence-based medicine is available from the US Agency for Healthcare Research and Quality and the Canadian Agency for Drugs and Technologies in Health
doi:10.1371/journal.pmed.0040078
PMCID: PMC1831728  PMID: 17388659
8.  Effect of Water, Sanitation, and Hygiene on the Prevention of Trachoma: A Systematic Review and Meta-Analysis 
PLoS Medicine  2014;11(2):e1001605.
Matthew Freeman and colleagues identified 86 individual studies that reported a measure of the effect of water, sanitation, and hygiene on trachoma and conducted 15 meta-analyses for specific exposure-outcome pairs.
Please see later in the article for the Editors' Summary
Background
Trachoma is the world's leading cause of infectious blindness. The World Health Organization (WHO) has endorsed the SAFE strategy in order to eliminate blindness due to trachoma by 2020 through “surgery,” “antibiotics,” “facial cleanliness,” and “environmental improvement.” While the S and A components have been widely implemented, evidence and specific targets are lacking for the F and E components, of which water, sanitation, and hygiene (WASH) are critical elements. Data on the impact of WASH on trachoma are needed to support policy and program recommendations. Our objective was to systematically review the literature and conduct meta-analyses where possible to report the effects of WASH conditions on trachoma and identify research gaps.
Methods and Findings
We systematically searched PubMed, Embase, ISI Web of Knowledge, MedCarib, Lilacs, REPIDISCA, DESASTRES, and African Index Medicus databases through October 27, 2013 with no restrictions on language or year of publication. Studies were eligible for inclusion if they reported a measure of the effect of WASH on trachoma, either active disease indicated by observed signs of trachomatous inflammation or Chlamydia trachomatis infection diagnosed using PCR. We identified 86 studies that reported a measure of the effect of WASH on trachoma. To evaluate study quality, we developed a set of criteria derived from the GRADE methodology. Publication bias was assessed using funnel plots. If three or more studies reported measures of effect for a comparable WASH exposure and trachoma outcome, we conducted a random-effects meta-analysis. We conducted 15 meta-analyses for specific exposure-outcome pairs. Access to sanitation was associated with lower trachoma as measured by the presence of trachomatous inflammation-follicular or trachomatous inflammation-intense (TF/TI) (odds ratio [OR] 0.85, 95% CI 0.75–0.95) and C. trachomatis infection (OR 0.67, 95% CI 0.55–0.78). Having a clean face was significantly associated with reduced odds of TF/TI (OR 0.42, 95% CI 0.32–0.52), as were facial cleanliness indicators lack of ocular discharge (OR 0.42, 95% CI 0.23–0.61) and lack of nasal discharge (OR 0.62, 95% CI 0.52–0.72). Facial cleanliness indicators were also associated with reduced odds of C. trachomatis infection: lack of ocular discharge (OR 0.40, 95% CI 0.31–0.49) and lack of nasal discharge (OR 0.56, 95% CI 0.37–0.76). Other hygiene factors found to be significantly associated with reduced TF/TI included face washing at least once daily (OR 0.76, 95% CI 0.57–0.96), face washing at least twice daily (OR 0.85, 95% CI 0.80–0.90), soap use (OR 0.76, 95% CI 0.59–0.93), towel use (OR 0.65, 95% CI 0.53–0.78), and daily bathing practices (OR 0.76, 95% CI 0.53–0.99). Living within 1 km of a water source was not found to be significantly associated with TF/TI or C. trachomatis infection, and the use of sanitation facilities was not found to be significantly associated with TF/TI.
Conclusions
We found strong evidence to support F and E components of the SAFE strategy. Though limitations included moderate to high heterogenity, low study quality, and the lack of standard definitions, these findings support the importance of WASH in trachoma elimination strategies and the need for the development of standardized approaches to measuring WASH in trachoma control programs.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Trachoma is a bacterial eye infection, which if left untreated may lead to irreversible blindness. Repeated infections over many years cause scarring on the eyelid, making the eyelashes turn inward. This causes pain and damage to the cornea at the front of the eye, which eventually leads to loss of vision. The disease is most common in rural areas in low-income countries, specifically sub-Saharan Africa. It spreads easily through contact with the discharge from an infected eye or nose, by hands, or by flies landing on the face. Women and children are more often affected than men. Trachoma is the world's leading cause of preventable blindness. A global alliance, led by The World Health Organization, is aiming to eliminate trachoma by 2020 by adopting the SAFE strategy. There are four components of this strategy. Two relate to treating the disease—“surgery” and “antibiotics.” The other two components relate to long-term prevention by promoting “facial” cleanliness and “environmental” changes (for example improving access to water and sanitation or reducing the breeding grounds for flies).
Why Was This Study Done?
The SAFE approach has been very successful in reducing the number of people with trachoma from 84 million in 2003 to 21.4 million in 2012. However, it is widely recognized that efforts need to be scaled up to reach the 2020 goal. Furthermore, if current improvements are to be sustained, then more attention needs to be given to the “F” and “E” elements and effective prevention. This study aimed to identify the most effective ways to improve hygiene, sanitation, and access to water for better trachoma control, and to find better ways of monitoring progress. The overall goal was to summarize the evidence in order to devise strategic and cost-effective approaches to trachoma prevention.
What Did the Researchers Do and Find?
The researchers conducted a systematic review, which involved first identifying and then assessing the quality of all of the research published on this topic. They then carried out a statistical analysis of the combined data from these studies, with the aim of drawing more robust conclusions (a meta-analysis). The analysis involved 15 different water, sanitation, and hygiene exposures (either hardware or practices, as determined by what was available in the literature) to determine which had the biggest impact on reducing the levels of trachoma. Most of the data came from studies carried out in Africa. The findings suggested that 11 of these exposures made a significant difference to the risk of infection or clinical symptoms of the disease. Improving personal hygiene had the greatest impact. Effective measures included face washing once or twice a day, using soap, using a towel, and daily bathing. Similarly, access to a sanitation facility, rather than open ground, also had a positive impact. The researchers also analyzed the data relating to water access. However, the studies so far have not yet measured this in a way that addresses the issues relevant to trachoma infection. Most studies have looked at whether the distance from a water source has an impact (and it seems it does not), whereas it may be more important to assess whether people have access to clean water or to enough water to wash. Many of these analyses require additional research to further clarify the impact of individual water, sanitation, and hygiene exposure on disease.
What Do These Findings Mean?
Overall, the results support that notion that water, sanitation, and hygiene are important components of an integrated strategy to control trachoma. Based on the research available to date, the two most effective ways are face washing and having access to a household-level sanitation facility, typically a simple pit latrine. The findings also point to ways in which current policy could be improved. Firstly, public health guidance should be placing greater emphasis on keeping the face clean. Current advice tends to focus on washing with clean water, but use of soap appears more effective. There are also opportunities for organizations to collaborate in this area. For example, organizations focusing on the prevention of diarrhea in children, which promote handwashing, could at the same time campaign for face washing to reduce transmission of trachoma. The second policy area to target is access to good quality sanitation. Such policy initiatives need to be better resourced in countries where trachoma is a problem. For example, although sub-Saharan Africa has the world's highest burden of trachoma, more than 50% of households there still do not have access to any sanitation facility.
There were a number of limitations to this study, which may affect the strength of the conclusions. The researchers found that many studies on this topic were observational, meaning that they did not assess an intervention and employ a control group, thus they are of limited rigor for assessing the impact of a water, sanitation, and hygiene intervention on trachoma. There was also a lot of variation in the way that different studies had defined and measured improvements to water, sanitation, and hygiene access. This made it difficult to make comparisons. Standard methods and indicators need to be developed for this purpose. The study also highlighted gaps in the research. More work is required to determine precisely what is needed in terms of access to water to reduce the incidence of trachoma. Similarly, in terms of improving sanitation, it is still unclear whether ensuring every household has a simple, onsite facility would be more effective than providing clean communal facilities. The potential role of schools in promoting relevant public health measures also needs investigation.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1001605.
WHO provides information on trachoma (in several languages)
The US Centers for Disease Control and Prevention provide information on trachoma
International Trachoma Initiative is dedicated to the goal of elimination of blinding trachoma
The Carter Center: Trachoma Control Program has a Trachoma Health Education Materials Library
WASHNTD has an online manual resource for NTDs for WASH policy and programming
doi:10.1371/journal.pmed.1001605
PMCID: PMC3934994  PMID: 24586120
9.  Systematic Reviews and Meta-analysis: Understanding the Best Evidence in Primary Healthcare 
Healthcare decisions for individual patients and for public health policies should be informed by the best available research evidence. The practice of evidence-based medicine is the integration of individual clinical expertise with the best available external clinical evidence from systematic research and patient's values and expectations. Primary care physicians need evidence for both clinical practice and for public health decision making. The evidence comes from good reviews which is a state-of-the-art synthesis of current evidence on a given research question. Given the explosion of medical literature, and the fact that time is always scarce, review articles play a vital role in decision making in evidence-based medical practice. Given that most clinicians and public health professionals do not have the time to track down all the original articles, critically read them, and obtain the evidence they need for their questions, systematic reviews and clinical practice guidelines may be their best source of evidence. Systematic reviews aim to identify, evaluate, and summarize the findings of all relevant individual studies over a health-related issue, thereby making the available evidence more accessible to decision makers. The objective of this article is to introduce the primary care physicians about the concept of systematic reviews and meta-analysis, outlining why they are important, describing their methods and terminologies used, and thereby helping them with the skills to recognize and understand a reliable review which will be helpful for their day-to-day clinical practice and research activities.
doi:10.4103/2249-4863.109934
PMCID: PMC3894019  PMID: 24479036
Evidence-based medicine; meta-analysis; primary care; systematic review
10.  Risk of Bias in Systematic Reviews of Non-Randomized Studies of Adverse Cardiovascular Effects of Thiazolidinediones and Cyclooxygenase-2 Inhibitors: Application of a New Cochrane Risk of Bias Tool 
PLoS Medicine  2016;13(4):e1001987.
Background
Systematic reviews of the effects of healthcare interventions frequently include non-randomized studies. These are subject to confounding and a range of other biases that are seldom considered in detail when synthesizing and interpreting the results. Our aims were to assess the reliability and usability of a new Cochrane risk of bias (RoB) tool for non-randomized studies of interventions and to determine whether restricting analysis to studies with low or moderate RoB made a material difference to the results of the reviews.
Methods and Findings
We selected two systematic reviews of population-based, controlled non-randomized studies of the relationship between the use of thiazolidinediones (TZDs) and cyclooxygenase-2 (COX-2) inhibitors and major cardiovascular events. Two epidemiologists applied the Cochrane RoB tool and made assessments across the seven specified domains of bias for each of 37 component studies. Inter-rater agreement was measured using the weighted Kappa statistic. We grouped studies according to overall RoB and performed statistical pooling for (a) all studies and (b) only studies with low or moderate RoB. Kappa scores across the seven bias domains ranged from 0.50 to 1.0. In the COX-2 inhibitor review, two studies had low overall RoB, 14 had moderate RoB, and five had serious RoB. In the TZD review, six studies had low RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. The pooled odds ratios for myocardial infarction, heart failure, and death for rosiglitazone versus pioglitazone remained significantly elevated when analyses were confined to studies with low or moderate RoB. However, the estimate for myocardial infarction declined from 1.14 (95% CI 1.07–1.24) to 1.06 (95% CI 0.99–1.13) when analysis was confined to studies with low RoB. Estimates of pooled relative risks of cardiovascular events with COX-2 inhibitors compared with no nonsteroidal anti-inflammatory drug changed little when analyses were confined to studies with low or moderate RoB. The exception was a rise in the relative risk associated with ibuprofen from 1.07 (95% CI 0.97–1.18) to 1.14 (95% CI 1.03–1.26). The main limitation of our study was testing the instrument on a narrow range of pharmacoepidemiological studies; we cannot assume our findings extend to a broader range of interventions and settings.
Conclusions
The Cochrane RoB tool highlighted a wide range of risks of bias in studies included in two widely cited reviews and had the potential to change the conclusions of the reviews. Systematic reviews that incorporate non-randomized studies of medical interventions should include a detailed assessment of RoB for each included study.
David Henry and colleagues re-evaluate findings from two systematic reviews using the new ACROBAT-NRSI bias assessment tool for non-randomized studies.
Editors' Summary
Background
In the past, clinicians used their own experience to help them make decisions about the best treatments (interventions) for their patients. Nowadays, “evidence-based medicine”—largely based on findings from randomized controlled trials (RCTs)—guides most clinical decisions. RCTs—studies that compare outcomes in groups of patients chosen at random to receive different interventions—are the best way to assess the efficacy of an intervention (the performance of a treatment under ideal conditions), but individual trials often fail to show a statistically significant difference (a difference unlikely to have arisen by chance) between two interventions. Significant differences between interventions can be detected, however, by undertaking a systematic review (a study that identifies all the RCTs on a given intervention using predefined criteria) and a meta-analysis (a statistical technique for combining, or “synthesizing,” the findings from several independent RCTs).
Why Was This Study Done?
Systematic reviews of healthcare interventions can also include non-randomized studies, which use administrative databases to identify people receiving different interventions and electronic health records to determine clinical outcomes. However, non-randomized studies of interventions are prone to many “biases” that affect the accuracy of their findings. For example, a potential bias in non-randomized studies is “confounding,” the possibility that an unmeasured characteristic shared by the people receiving a specific intervention, rather than the intervention itself, is responsible for the observed outcome. When undertaking systematic reviews and meta-analyses, it is essential to measure the risk of bias (RoB) in each individual study included in the review and meta-analysis. But, although a widely used tool is available for measuring RoB in RCTs, bias is seldom considered in detail when synthesizing the results of non-randomized studies of interventions. Here, the researchers assess the reliability and usability of ACROBAT-NRSI, a tool developed by Cochrane (an organization that promotes evidence-informed health decision-making) for the assessment of RoB in non-randomized intervention studies. ACROBAT-NRSI assists authors in identifying potential concerns across seven bias domains and assesses the overall RoB of individual non-randomized intervention studies.
What Did the Researchers Do and Find?
Two of the researchers independently applied the ACROBAT-NRSI process to 37 papers included in two widely cited systematic reviews of non-randomized studies of the relationship between the use of thiazolidinediones (drugs used to treat diabetes, such as rosiglitazone and pioglitazone) and cyclooxygenase-2 (COX-2) inhibitors (nonsteroidal anti-inflammatory drugs [NSAIDs] such as ibuprofen) and major cardiovascular events (heart attack [myocardial infarction] and heart failure). The two researchers largely agreed on their RoB assessments (good inter-rater agreement), which, after training and early experience, took roughly 2.5 hours to complete for each study. In the thiazolidinedione review, six studies had low overall RoB, four had moderate RoB, four had serious RoB, and two had critical RoB. In the COX-2 inhibitor review, two studies low overall RoB, fourteen had moderate RoB, and five had serious RoB. When the researchers restricted meta-analysis to studies with low or moderate RoB, estimates of the pooled relative risks of cardiovascular events with COX-2 inhibitors (compared with no NSAID) changed little, except for a rise in the relative risk associated with ibuprofen. Finally, although the risk estimates for myocardial infarction, heart failure, and death for rosiglitazone compared with pioglitazone remained significantly raised when analyses were confined to studies with low or moderate RoB, there was no significantly increased risk of myocardial infarction when the analysis was confined to studies with low RoB.
What Do These Findings Mean?
These findings show that there was considerable variability in RoB among the studies included in two systematic reviews of non-randomized intervention studies. Although all 37 studies included in these reviews were originally considered to be of sufficiently high quality for inclusion using less comprehensive—or less RoB-focused—critical appraisal tools, only eight were judged to have low RoB using ACROBAT-NRSI. Notably, exclusion of studies with moderate, serious, or critical RoB resulted in clinically important changes to some of the conclusions of the original reviews. Because the researchers considered only two systematic reviews, their findings may not be generalizable—ACROBAT-NRSI needs further testing across a range of study types. Moreover, because the tool is designed to be used within a team setting, studies are needed to investigate whether the performance of the tool depends on the team’s skill mix. Importantly, however, these findings highlight the importance of including a detailed RoB assessment for each study included in systematic reviews of non-randomized studies of medical interventions.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001987.
More information about ACROBAT-NRSI (A Cochrane Risk of Bias Assessment Tool for Non-Randomized Studies of Interventions) is available; the main Cochrane website provides information about Cochrane and its work; the Cochrane Handbook for Systematic Reviews of Interventions has a chapter on including non-randomized studies in systematic reviews
Wikipedia has pages on evidence-based medicine, clinical trials, systematic review, and meta-analysis (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
ClinicalTrials.gov, the US National Institutes of Health clinical trials registry, provides additional background information about clinical trials
doi:10.1371/journal.pmed.1001987
PMCID: PMC4821619  PMID: 27046153
11.  Risks and Benefits of Nalmefene in the Treatment of Adult Alcohol Dependence: A Systematic Literature Review and Meta-Analysis of Published and Unpublished Double-Blind Randomized Controlled Trials 
PLoS Medicine  2015;12(12):e1001924.
Background
Nalmefene is a recent option in alcohol dependence treatment. Its approval was controversial. We conducted a systematic review and meta-analysis of the aggregated data (registered as PROSPERO 2014:CRD42014014853) to compare the harm/benefit of nalmefene versus placebo or active comparator in this indication.
Methods and Findings
Three reviewers searched for published and unpublished studies in Medline, the Cochrane Library, Embase, ClinicalTrials.gov, Current Controlled Trials, and bibliographies and by mailing pharmaceutical companies, the European Medicines Agency (EMA), and the US Food and Drug Administration. Double-blind randomized clinical trials evaluating nalmefene to treat adult alcohol dependence, irrespective of the comparator, were included if they reported (1) health outcomes (mortality, accidents/injuries, quality of life, somatic complications), (2) alcohol consumption outcomes, (3) biological outcomes, or (4) treatment safety outcomes, at 6 mo and/or 1 y. Three authors independently screened the titles and abstracts of the trials identified. Relevant trials were evaluated in full text. The reviewers independently assessed the included trials for methodological quality using the Cochrane Collaboration tool for assessing risk of bias. On the basis of the I2 index or the Cochrane’s Q test, fixed or random effect models were used to estimate risk ratios (RRs), mean differences (MDs), or standardized mean differences (SMDs) with 95% CIs. In sensitivity analyses, outcomes for participants who were lost to follow-up were included using baseline observation carried forward (BOCF); for binary measures, patients lost to follow-up were considered equal to failures (i.e., non-assessed patients were recorded as not having responded in both groups). Five randomized controlled trials (RCTs) versus placebo, with a total of 2,567 randomized participants, were included in the main analysis. None of these studies was performed in the specific population defined by the EMA approval of nalmefene, i.e., adults with alcohol dependence who consume more than 60 g of alcohol per day (for men) or more than 40 g per day (for women). No RCT compared nalmefene with another medication. Mortality at 6 mo (RR = 0.39, 95% CI [0.08; 2.01]) and 1 y (RR = 0.98, 95% CI [0.04; 23.95]) and quality of life at 6 mo (SF-36 physical component summary score: MD = 0.85, 95% CI [−0.32; 2.01]; SF-36 mental component summary score: MD = 1.01, 95% CI [−1.33; 3.34]) were not different across groups. Other health outcomes were not reported. Differences were encountered for alcohol consumption outcomes such as monthly number of heavy drinking days at 6 mo (MD = −1.65, 95% CI [−2.41; −0.89]) and at 1 y (MD = −1.60, 95% CI [−2.85; −0.35]) and total alcohol consumption at 6 mo (SMD = −0.20, 95% CI [−0.30; −0.10]). An attrition bias could not be excluded, with more withdrawals for nalmefene than for placebo, including more withdrawals for safety reasons at both 6 mo (RR = 3.65, 95% CI [2.02; 6.63]) and 1 y (RR = 7.01, 95% CI [1.72; 28.63]). Sensitivity analyses showed no differences for alcohol consumption outcomes between nalmefene and placebo, but the weight of these results should not be overestimated, as the BOCF approach to managing withdrawals was used.
Conclusions
The value of nalmefene for treatment of alcohol addiction is not established. At best, nalmefene has limited efficacy in reducing alcohol consumption.
In a systematic review and meta-analysis, Florian Naudet and colleagues assess whether medication with the opioid antagonist nalmefene can reduce consumption and other outcomes of alcohol addiction.
Editors' Summary
Background
Many people enjoy an occasional alcoholic drink. But because alcohol is an addictive substance, some people (around one in 12 people in the US, for example) develop alcohol dependency (alcoholism). Such people have an excessive desire to drink or have lost control over their alcohol use, and may find it hard to relax or enjoy themselves without having a drink. As well as becoming psychologically dependent on alcohol, they can become physically dependent and may show withdrawal symptoms such as sweating, shaking, and nausea—or even delirium tremens, a psychotic condition that involves tremors, hallucinations, anxiety, and disorientation—when they attempt to reduce their drinking. Indeed, severely dependent drinkers often drink to relieve their withdrawal symptoms (“relief drinking”). Although alcohol dependency sometimes runs in families, it can also be triggered by stressful events, and the condition can damage health, emotional stability, finances, careers, and relationships.
Why Was This Study Done?
To reduce harm, alcohol-dependent individuals are usually advised to abstain from drinking, but controlled (moderate) drinking may also be helpful. To help people reduce their alcohol consumption, the European Medicines Agency recently approved nalmefene—a drug that blocks the body’s opioid receptors and reduces the craving for alcohol—for use in the treatment of alcohol dependence in adults who consume more than 60 g (for men) or 40 g (for women) of alcohol per day (a small glass of wine contains about 12 g of alcohol; a can of beer contains about 16 g). However, several expert bodies have concluded that nalmefene shows no benefit over naltrexone, an older treatment for alcohol dependency, and do not recommend its use for this indication. Here, the researchers investigate the risks and benefits of nalmefene in the treatment of alcohol dependency in adults by undertaking a systematic review and meta-analysis of double-blind randomized controlled trials (RCTs) of nalmefene for this indication. A systematic review uses predefined criteria to identify all the research on a given topic, and a meta-analysis combines the results of several studies; a double-blind RCT compares outcomes in people chosen at random to receive different treatments without the researchers or the participants knowing who received which treatment until the end of the trial.
What Did the Researchers Do and Find?
The researchers identified five RCTs that met the criteria for inclusion in their study. All five RCTs (which involved 2,567 participants) compared the effects of nalmefene with a placebo (dummy drug); none was undertaken in the population specified by the European Medicines Agency approval. Among the health outcomes examined in the meta-analysis, there were no differences between participants taking nalmefene and those taking placebo in mortality (death) after six months or one year of treatment, in the quality of life at six months, or in a summary score indicating mental health at six months. The RCTs included in the meta-analysis did not report other health outcomes such as accidents. Participants taking nalmefene had fewer heavy drinking days per month at six months and one year of treatment than participants taking placebo, and their total alcohol consumption was lower. However, more people withdrew from the nalmefene groups than from the placebo groups, often for safety reasons. Thus, attrition bias—selection bias caused by systematic differences between groups in withdrawals from a study that can affect the accuracy of the study’s findings—cannot be excluded. Indeed, when the researchers undertook an analysis in which they allowed for withdrawals, the alcohol consumption outcomes did not differ between the treatment groups.
What Do These Findings Mean?
These findings show that there is no high-grade evidence currently available from RCTs to support the use of nalmefene for harm reduction among people being treated for alcohol dependency. In addition, they provide little evidence to support the use of nalmefene to reduce alcohol consumption among this population. Thus, the value of nalmefene for the treatment of alcohol addiction is not established. Importantly, these findings reveal a lack of information on clinically relevant outcomes in the evidence that led to nalmefene approval by the European Medicines Agency. Thus, these findings also call into question the decisions of this and other regulatory and advisory bodies that have approved nalmefene on the basis of the available evidence from RCTs, and highlight the need for further RCTs of nalmefene compared to placebo and naltrexone for the indication specified in the market approval.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001924.
The US National Institute on Alcohol Abuse and Alcoholism has information about alcohol and its effects on health (including alcohol use disorder, another name for alcohol dependency); it provides interactive worksheets to help people evaluate their drinking and decide whether and how to make a change
The UK National Health Service Choices website provides detailed information about drinking and alcohol and about alcohol dependency (including a personal story about alcohol misuse), and tools for calculating alcohol consumption
The US National Council on Alcoholism and Drug Dependence provides information about alcohol addiction and a self-test for alcohol dependence
Drinkaware is a UK-based non-profit organization that aims to improve the UK’s drinking habits; its website provides information on alcohol dependence and on other aspects of alcohol and health, and a tool for calculating alcohol intake
MedlinePlus provides links to many other resources on alcohol and on alcoholism and alcohol abuse
Wikipedia has pages on nalmefene and on naltrexone (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
Details of the European Medicine Agency approval of nalmefene are available
More information about this study is available
doi:10.1371/journal.pmed.1001924
PMCID: PMC4687857  PMID: 26694529
12.  Recent meta-analyses neglect previous systematic reviews and meta-analyses about the same topic: a systematic examination 
BMC Medicine  2015;13:82.
Background
As the number of systematic reviews is growing rapidly, we systematically investigate whether meta-analyses published in leading medical journals present an outline of available evidence by referring to previous meta-analyses and systematic reviews.
Methods
We searched PubMed for recent meta-analyses of pharmacological treatments published in high impact factor journals. Previous systematic reviews and meta-analyses were identified with electronic searches of keywords and by searching reference sections. We analyzed the number of meta-analyses and systematic reviews that were cited, described and discussed in each recent meta-analysis. Moreover, we investigated publication characteristics that potentially influence the referencing practices.
Results
We identified 52 recent meta-analyses and 242 previous meta-analyses on the same topics. Of these, 66% of identified previous meta-analyses were cited, 36% described, and only 20% discussed by recent meta-analyses. The probability of citing a previous meta-analysis was positively associated with its publication in a journal with a higher impact factor (odds ratio, 1.49; 95% confidence interval, 1.06 to 2.10) and more recent publication year (odds ratio, 1.19; 95% confidence interval 1.03 to 1.37). Additionally, the probability of a previous study being described by the recent meta-analysis was inversely associated with the concordance of results (odds ratio, 0.38; 95% confidence interval, 0.17 to 0.88), and the probability of being discussed was increased for previous studies that employed meta-analytic methods (odds ratio, 32.36; 95% confidence interval, 2.00 to 522.85).
Conclusions
Meta-analyses on pharmacological treatments do not consistently refer to and discuss findings of previous meta-analyses on the same topic. Such neglect can lead to research waste and be confusing for readers. Journals should make the discussion of related meta-analyses mandatory.
Electronic supplementary material
The online version of this article (doi:10.1186/s12916-015-0317-4) contains supplementary material, which is available to authorized users.
doi:10.1186/s12916-015-0317-4
PMCID: PMC4411715  PMID: 25889502
Meta-analysis; Methodology; PRISMA statement; Research waste; Systematic review
13.  Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to conduct an evidence-based assessment of home telehealth technologies for patients with chronic obstructive pulmonary disease (COPD) in order to inform recommendations regarding the access and provision of these services in Ontario. This analysis was one of several analyses undertaken to evaluate interventions for COPD. The perspective of this assessment was that of the Ontario Ministry of Health and Long-Term Care, a provincial payer of medically necessary health care services.
Clinical Need: Condition and Target Population
Canada is facing an increase in chronic respiratory diseases due in part to its aging demographic. The projected increase in COPD will put a strain on health care payers and providers. There is therefore an increasing demand for telehealth services that improve access to health care services while maintaining or improving quality and equality of care. Many telehealth technologies however are in the early stages of development or diffusion and thus require study to define their application and potential harms or benefits. The Medical Advisory Secretariat (MAS) therefore sought to evaluate telehealth technologies for COPD.
Technology
Telemedicine (or telehealth) refers to using advanced information and communication technologies and electronic medical devices to support the delivery of clinical care, professional education, and health-related administrative services.
Generally there are 4 broad functions of home telehealth interventions for COPD:
to monitor vital signs or biological health data (e.g., oxygen saturation),
to monitor symptoms, medication, or other non-biologic endpoints (e.g., exercise adherence),
to provide information (education) and/or other support services (such as reminders to exercise or positive reinforcement), and
to establish a communication link between patient and provider.
These functions often require distinct technologies, although some devices can perform a number of these diverse functions. For the purposes of this review, MAS focused on home telemonitoring and telephone only support technologies.
Telemonitoring (or remote monitoring) refers to the use of medical devices to remotely collect a patient’s vital signs and/or other biologic health data and the transmission of those data to a monitoring station for interpretation by a health care provider.
Telephone only support refers to disease/disorder management support provided by a health care provider to a patient who is at home via telephone or videoconferencing technology in the absence of transmission of patient biologic data.
Research Questions
What is the effectiveness, cost-effectiveness, and safety of home telemonitoring compared with usual care for patients with COPD?
What is the effectiveness, cost-effectiveness, and safety of telephone only support programs compared with usual care for patients with COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on November 3, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2000 until November 3, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, and then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low, or very low according to GRADE methodology.
Inclusion Criteria – Question #1
frequent transmission of a patient’s physiological data collected at home and without a health care professional physically present to health care professionals for routine monitoring through the use of a communication technology;
monitoring combined with a coordinated management and feedback system based on transmitted data;
telemonitoring as a key component of the intervention (subjective determination);
usual care as provided by the usual care provider for the control group;
randomized controlled trials (RCTs), controlled clinical trials (CCTs), systematic reviews, and/or meta-analyses;
published between January 1, 2000 and November 3, 2010.
Inclusion Criteria – Question #2
scheduled or frequent contact between patient and a health care professional via telephone or videoconferencing technology in the absence of transmission of patient physiological data;
monitoring combined with a coordinated management and feedback system based on transmitted data;
telephone support as a key component of the intervention (subjective determination);
usual care as provided by the usual care provider for the control group;
RCTs, CCTs, systematic reviews, and/or meta-analyses;
published between January 1, 2000 and November 3, 2010.
Exclusion Criteria
published in a language other than English;
intervention group (and not control) receiving some form of home visits by a medical professional, typically a nurse (i.e., telenursing) beyond initial technology set-up and education, to collect physiological data, or to somehow manage or treat the patient;
not recording patient or health system outcomes (e.g., technical reports testing accuracy, reliability or other development-related outcomes of a device, acceptability/feasibility studies, etc.);
not using an independent control group that received usual care (e.g., studies employing historical or periodic controls).
Outcomes of Interest
hospitalizations (primary outcome)
mortality
emergency department visits
length of stay
quality of life
other […]
Subgroup Analyses (a priori)
length of intervention (primary)
severity of COPD (primary)
Quality of Evidence
The quality of evidence assigned to individual studies was determined using a modified CONSORT Statement Checklist for Randomized Controlled Trials. (1) The CONSORT Statement was adapted to include 3 additional quality measures: the adequacy of control group description, significant differential loss to follow-up between groups, and greater than or equal to 30% study attrition. Individual study quality was defined based on total scores according to the CONSORT Statement checklist: very low (0 to < 40%), low (≥ 40 to < 60%), moderate (≥ 60 to < 80%), and high (≥ 80 to 100%).
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Six publications, representing 5 independent trials, met the eligibility criteria for Research Question #1. Three trials were RCTs reported across 4 publications, whereby patients were randomized to home telemonitoring or usual care, and 2 trials were CCTs, whereby patients or health care centers were nonrandomly assigned to intervention or usual care.
A total of 310 participants were studied across the 5 included trials. The mean age of study participants in the included trials ranged from 61.2 to 74.5 years for the intervention group and 61.1 to 74.5 years for the usual care group. The percentage of men ranged from 40% to 64% in the intervention group and 46% to 72% in the control group.
All 5 trials were performed in a moderate to severe COPD patient population. Three trials initiated the intervention following discharge from hospital. One trial initiated the intervention following a pulmonary rehabilitation program. The final trial initiated the intervention during management of patients at an outpatient clinic.
Four of the 5 trials included oxygen saturation (i.e., pulse oximetry) as one of the biological patient parameters being monitored. Additional parameters monitored included forced expiratory volume in one second, peak expiratory flow, and temperature.
There was considerable clinical heterogeneity between trials in study design, methods, and intervention/control. In relation to the telemonitoring intervention, 3 of the 5 included studies used an electronic health hub that performed multiple functions beyond the monitoring of biological parameters. One study used only a pulse oximeter device alone with modem capabilities. Finally, in 1 study, patients measured and then forwarded biological data to a nurse during a televideo consultation. Usual care varied considerably between studies.
Only one trial met the eligibility criteria for Research Question #2. The included trial was an RCT that randomized 60 patients to nurse telephone follow-up or usual care (no telephone follow-up). Participants were recruited from the medical department of an acute-care hospital in Hong Kong and began receiving follow-up after discharge from the hospital with a diagnosis of COPD (no severity restriction). The intervention itself consisted of only two 10-to 20-minute telephone calls, once between days 3 to 7 and once between days 14 to 20, involving a structured, individualized educational and supportive programme led by a nurse that focused on 3 components: assessment, management options, and evaluation.
Regarding Research Question #1:
Low to very low quality evidence (according to GRADE) finds non-significant effects or conflicting effects (of significant or non-significant benefit) for all outcomes examined when comparing home telemonitoring to usual care.
There is a trend towards significant increase in time free of hospitalization and use of other health care services with home telemonitoring, but these findings need to be confirmed further in randomized trials of high quality.
There is severe clinical heterogeneity between studies that limits summary conclusions.
The economic impact of home telemonitoring is uncertain and requires further study.
Home telemonitoring is largely dependent on local information technologies, infrastructure, and personnel, and thus the generalizability of external findings may be low. Jurisdictions wishing to replicate home telemonitoring interventions should likely test those interventions within their jurisdictional framework before adoption, or should focus on home-grown interventions that are subjected to appropriate evaluation and proven effective.
Regarding Research Question #2:
Low quality evidence finds significant benefit in favour of telephone-only support for self-efficacy and emergency department visits when compared to usual care, but non-significant results for hospitalizations and hospital length of stay.
There are very serious issues with the generalizability of the evidence and thus additional research is required.
PMCID: PMC3384362  PMID: 23074421
14.  Epidermal growth factor receptor targeted therapy in stages III and IV head and neck cancer 
Current Oncology  2010;17(3):37-48.
Question
What are the benefits associated with the use of anti–epidermal growth factor receptor (anti-egfr) therapies in squamous cell carcinoma of the head and neck (hnscc)? Anti-egfr therapies of interest included cetuximab, gefitinib, lapatinib, zalutumumab, erlotinib, and panitumumab.
Perspectives
Head-and-neck cancer includes malignant tumours arising from a variety of sites in the upper aerodigestive tract. The most common histologic type is squamous cell carcinoma, and most common sites are the oral cavity, the oropharynx, the hypopharynx, and the larynx. Worldwide, hnscc is the sixth most common neoplasm, and despite advances in therapy, long-term survival in hnscc patients is poor. Primary surgery followed by chemoradiation, or primary chemoradiation, are the standard treatment options for patients with locally advanced (stages iii–ivb) hnscc; however, meta-analytic data indicate that the benefit of concurrent platinum-based chemotherapy disappears in patients over the age of 70 years.
Cetuximab is a monoclonal antibody approved for use in combination with radiation in the treatment of patients with untreated locally advanced hnscc and as monotherapy for patients with recurrent or metastatic (stage ivc) hnscc who have progressed on platinum-based therapy.
Given the interest in anti-egfr agents in advanced hnscc, the Head and Neck Cancer Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) chose to systematically review the literature pertaining to this topic so as to develop evidence-based recommendations for treatment.
Outcomes
Outcomes of interest included overall and progression-free survival, quality of life, tumour response rate and duration, and the toxicity associated with the use of anti-egfr therapies.
Methodology
The medline, embase, and Cochrane Library databases, the American Society of Clinical Oncology online conference proceedings, the Canadian Medical Association InfoBase, and the National Guidelines Clearinghouse were systematically searched to locate primary articles and practice guidelines. The reference lists from relevant review articles were searched for additional trials. All evidence was reviewed, and that evidence informed the development of the clinical practice guideline. The resulting recommendations were approved by the Report Approval Panel of the pebc, and by the Head and Neck Cancer dsg. An external review by Ontario practitioners completed the final phase of the review process. Feedback from all parties was incorporated to create the final practice guideline.
Results
The electronic search identified seventy-four references that were reviewed for inclusion. Only four phase iii trials met the inclusion criteria for the present guideline. No practice guidelines, systematic reviews, or meta-analyses were found during the course of the literature search.
The randomized controlled trials (rcts) involved three distinct patient populations: those with locally advanced hnscc being treated for cure, those with incurable advanced recurrent or metastatic hnscc being treated with first-line platinum-based chemotherapy, and those with incurable advanced recurrent or metastatic hnscc who had disease progression despite, or who were unsuitable for, first-line platinum-based chemotherapy.
Practice Guideline
These recommendations apply to adult patients with locally advanced (nonmetastatic stages iii–ivb) or recurrent or metastatic (stage ivc) hnscc.
Platinum-based chemoradiation remains the current standard of care for treatment of locally advanced hnscc.
In patients with locally advanced hnscc who are medically unsuitable for concurrent platinumbased chemotherapy or who are over the age of 70 years (because concurrent chemotherapy does not appear to improve overall survival in this patient population), the addition of cetuximab to radical radiotherapy should be considered to improve overall survival, progression-free survival, and time to local recurrence.
Cetuximab in combination with platinum-based combination chemotherapy is superior to chemotherapy alone in patients with recurrent or metastatic hnscc, and is recommended to improve overall survival, progression-free survival, and response rate.
The role of anti-egfr therapies in the treatment of locally advanced hnscc is currently under study in large randomized trials, and patients with hnscc should continue to be offered clinical trials of novel agents aimed at improving outcomes.
Qualifying Statements
Chemoradiation is the current standard of care for patients with locally advanced hnscc, and to date, there is no evidence that compares cetuximab plus radiotherapy with chemoradiation, or that examines whether the addition of cetuximab to chemoradiation is of benefit in these patients. However, five ongoing trials are investigating the effect of the addition of egfr inhibitors concurrently with, before, or after chemoradiotherapy; those trials should provide direction about the best integration of cetuximab into standard treatment.
In patients with recurrent or metastatic hnscc who experience progressive disease despite, or who are unsuitable for, first-line platinum-based chemotherapy, gefitinib at doses of 250 mg or 500 mg daily, compared with weekly methotrexate, did not increase median overall survival [hazard ratio (hr): 1.22; 96% confidence interval (ci): 0.95 to 1.57; p = 0.12 (for 250 mg daily vs. weekly methotrexate); hr: 1.12; 95% ci: 0.87 to 1.43; p = 0.39 (for 500 mg daily vs. weekly methotrexate)] or objective response rate (2.7% for 250 mg and 7.6% for 500 mg daily vs. 3.9% for weekly methotrexate, p > 0.05). As compared with methotrexate, gefitinib was associated with an increased incidence of tumour hemorrhage (8.9% for 250 mg and 11.4% for 500 mg daily vs. 1.9% for weekly methotrexate).
PMCID: PMC2880902  PMID: 20567625
Head-and-neck cancer; epidermal growth factor receptor; egfr inhibitors; overall survival; progression-free survival; tumour response rate
15.  Information from Pharmaceutical Companies and the Quality, Quantity, and Cost of Physicians' Prescribing: A Systematic Review 
PLoS Medicine  2010;7(10):e1000352.
Geoff Spurling and colleagues report findings of a systematic review looking at the relationship between exposure to promotional material from pharmaceutical companies and the quality, quantity, and cost of prescribing. They fail to find evidence of improvements in prescribing after exposure, and find some evidence of an association with higher prescribing frequency, higher costs, or lower prescribing quality.
Background
Pharmaceutical companies spent $57.5 billion on pharmaceutical promotion in the United States in 2004. The industry claims that promotion provides scientific and educational information to physicians. While some evidence indicates that promotion may adversely influence prescribing, physicians hold a wide range of views about pharmaceutical promotion. The objective of this review is to examine the relationship between exposure to information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing.
Methods and Findings
We searched for studies of physicians with prescribing rights who were exposed to information from pharmaceutical companies (promotional or otherwise). Exposures included pharmaceutical sales representative visits, journal advertisements, attendance at pharmaceutical sponsored meetings, mailed information, prescribing software, and participation in sponsored clinical trials. The outcomes measured were quality, quantity, and cost of physicians' prescribing. We searched Medline (1966 to February 2008), International Pharmaceutical Abstracts (1970 to February 2008), Embase (1997 to February 2008), Current Contents (2001 to 2008), and Central (The Cochrane Library Issue 3, 2007) using the search terms developed with an expert librarian. Additionally, we reviewed reference lists and contacted experts and pharmaceutical companies for information. Randomized and observational studies evaluating information from pharmaceutical companies and measures of physicians' prescribing were independently appraised for methodological quality by two authors. Studies were excluded where insufficient study information precluded appraisal. The full text of 255 articles was retrieved from electronic databases (7,185 studies) and other sources (138 studies). Articles were then excluded because they did not fulfil inclusion criteria (179) or quality appraisal criteria (18), leaving 58 included studies with 87 distinct analyses. Data were extracted independently by two authors and a narrative synthesis performed following the MOOSE guidelines. Of the set of studies examining prescribing quality outcomes, five found associations between exposure to pharmaceutical company information and lower quality prescribing, four did not detect an association, and one found associations with lower and higher quality prescribing. 38 included studies found associations between exposure and higher frequency of prescribing and 13 did not detect an association. Five included studies found evidence for association with higher costs, four found no association, and one found an association with lower costs. The narrative synthesis finding of variable results was supported by a meta-analysis of studies of prescribing frequency that found significant heterogeneity. The observational nature of most included studies is the main limitation of this review.
Conclusions
With rare exceptions, studies of exposure to information provided directly by pharmaceutical companies have found associations with higher prescribing frequency, higher costs, or lower prescribing quality or have not found significant associations. We did not find evidence of net improvements in prescribing, but the available literature does not exclude the possibility that prescribing may sometimes be improved. Still, we recommend that practitioners follow the precautionary principle and thus avoid exposure to information from pharmaceutical companies.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
A prescription drug is a medication that can be supplied only with a written instruction (“prescription”) from a physician or other licensed healthcare professional. In 2009, 3.9 billion drug prescriptions were dispensed in the US alone and US pharmaceutical companies made US$300 billion in sales revenue. Every year, a large proportion of this revenue is spent on drug promotion. In 2004, for example, a quarter of US drug revenue was spent on pharmaceutical promotion. The pharmaceutical industry claims that drug promotion—visits from pharmaceutical sales representatives, advertisements in journals and prescribing software, sponsorship of meetings, mailed information—helps to inform and educate healthcare professionals about the risks and benefits of their products and thereby ensures that patients receive the best possible care. Physicians, however, hold a wide range of views about pharmaceutical promotion. Some see it as a useful and convenient source of information. Others deny that they are influenced by pharmaceutical company promotion but claim that it influences other physicians. Meanwhile, several professional organizations have called for tighter control of promotional activities because of fears that pharmaceutical promotion might encourage physicians to prescribe inappropriate or needlessly expensive drugs.
Why Was This Study Done?
But is there any evidence that pharmaceutical promotion adversely influences prescribing? Reviews of the research literature undertaken in 2000 and 2005 provide some evidence that drug promotion influences prescribing behavior. However, these reviews only partly assessed the relationship between information from pharmaceutical companies and prescribing costs and quality and are now out of date. In this study, therefore, the researchers undertake a systematic review (a study that uses predefined criteria to identify all the research on a given topic) to reexamine the relationship between exposure to information from pharmaceutical companies and the quality, quantity, and cost of physicians' prescribing.
What Did the Researchers Do and Find?
The researchers searched the literature for studies of licensed physicians who were exposed to promotional and other information from pharmaceutical companies. They identified 58 studies that included a measure of exposure to any type of information directly provided by pharmaceutical companies and a measure of physicians' prescribing behavior. They then undertook a “narrative synthesis,” a descriptive analysis of the data in these studies. Ten of the studies, they report, examined the relationship between exposure to pharmaceutical company information and prescribing quality (as judged, for example, by physician drug choices in response to clinical vignettes). All but one of these studies suggested that exposure to drug company information was associated with lower prescribing quality or no association was detected. In the 51 studies that examined the relationship between exposure to drug company information and prescribing frequency, exposure to information was associated with more frequent prescribing or no association was detected. Thus, for example, 17 out of 29 studies of the effect of pharmaceutical sales representatives' visits found an association between visits and increased prescribing; none found an association with less frequent prescribing. Finally, eight studies examined the relationship between exposure to pharmaceutical company information and prescribing costs. With one exception, these studies indicated that exposure to information was associated with a higher cost of prescribing or no association was detected. So, for example, one study found that physicians with low prescribing costs were more likely to have rarely or never read promotional mail or journal advertisements from pharmaceutical companies than physicians with high prescribing costs.
What Do These Findings Mean?
With rare exceptions, these findings suggest that exposure to pharmaceutical company information is associated with either no effect on physicians' prescribing behavior or with adverse affects (reduced quality, increased frequency, or increased costs). Because most of the studies included in the review were observational studies—the physicians in the studies were not randomly selected to receive or not receive drug company information—it is not possible to conclude that exposure to information actually causes any changes in physician behavior. Furthermore, although these findings provide no evidence for any net improvement in prescribing after exposure to pharmaceutical company information, the researchers note that it would be wrong to conclude that improvements do not sometimes happen. The findings support the case for reforms to reduce negative influence to prescribing from pharmaceutical promotion.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000352.
Wikipedia has pages on prescription drugs and on pharmaceutical marketing (note that Wikipedia is a free online encyclopedia that anyone can edit; available in several languages)
The UK General Medical Council provides guidelines on good practice in prescribing medicines
The US Food and Drug Administration provides information on prescription drugs and on its Bad Ad Program
Healthy Skepticism is an international nonprofit membership association that aims to improve health by reducing harm from misleading health information
The Drug Promotion Database was developed by the World Health Organization Department of Essential Drugs & Medicines Policy and Health Action International Europe to address unethical and inappropriate drug promotion
doi:10.1371/journal.pmed.1000352
PMCID: PMC2957394  PMID: 20976098
16.  Towards evidence‐based medicine for paediatricians 
To give the best care to patients and families, paediatricians need to integrate the highest quality scientific evidence with clinical expertise and the opinions of the family.1Archimedes seeks to assist practising clinicians by providing “evidence‐based” answers to common questions that are not at the forefront of research but are at the core of practice. In doing this, we are adapting a format that has been successfully developed by Kevin Mackway‐Jones and the group at the Emergency Medicine Journal—“BestBets”.
A word of warning. The topic summaries are not systematic reviews, although they are as exhaustive as a practising clinician can produce. They make no attempt to statistically aggregate the data, nor to search the grey, unpublished literature. What Archimedes offers is practical, best evidence‐based answers to practical, clinical questions.
The format of Archimedes may be familiar. A description of the clinical setting is followed by a structured clinical question. (These aid in focusing the mind, assisting searching2 and obtaining answers.3) A brief report of the search used follows—this has been performed in a hierarchical way, to search for the best quality evidence to answer the question (http://www.cebm.net). A table provides a summary of the evidence and key points of the critical appraisal. For further information on critical appraisal, and the measures of effect (such as the number needed to treat), books by Sackett4 and Moyer5 may help. To pull the information together, a commentary is provided, but to make it all much more accessible, a box provides the clinical bottom lines.
Electronics‐only topics that have been published on the BestBets site (www.bestbets.org) and may be of interest to paediatricians include the following.
Can steroids be used to reduce post tonsillectomy pain?
Readers wishing to submit their own questions—with best evidence answers—are encouraged to review those already proposed at www.bestbets.org. If your question still hasn't been answered, feel free to submit your summary according to the instructions for authors at www.archdischild.com. Three topics are covered in this issue of the journal:
Is teething the cause of minor ailments?
Should steroid creams be used in cases of labial fusion?
Does erythromycin cause pyloric stenosis?
References
1 Moyer VA, Ellior EJ. Preface. In: Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health. Issue 1. London: BMJ Books, 2000.
2 Richardson WS, Wilson MC, Nishikawa J, et al. The well‐built clinical question: a key to evidence‐based decisions. ACP J Club 1995;123:A12–13.
3 Bergus GR, Randall CS, Sinift SD, et al. Does the structure of clinical questions affect the outcome of curbside consultations with specialty colleagues? Arch Fam Med 2000;9:541–7.
4 Sackett DL, Starus S, Richardson WS, et al. Evidence‐based medicine. How to practice and teach EBM. San Diego: Harcourt‐Brace, 2000.
5 Moyer VA, Elliott EJ, Davis RL, et al, eds. Evidence based pediatrics and child health. Issue 1. London: BMJ Books, 2000.
Can: doing, using and replicating evidence‐based child health
The practice of evidence‐based child health is said to be the five‐step way of asking questions, acquiring information, appraising the evidence, applying the results and assessing our performance.
If the truth be known, for the vast majority of the time, most of us perform our clinical practice replicating what we have done previously. Most of the time this is based on the combination of excellent education, skilled interpretation of clinical findings, and good discussions with children and families. We hope that the education we rely on was (and remains) based on the best available scientific evidence. If it is, we are practising a form of “micro‐evidence‐based healthcare (EBHC)” (doing just step 4).
Sometimes, we question our knowledge (or more uncomfortably, someone does this for us), and will head off to top up our understanding of an area. This “using” mode, if we use well‐appraised resources to supply our thirst for information, will also promote the practice of evidence‐based care. This midi‐EBHC asks us to go through steps 1, 2 and 4.
Occasionally, we also actually need to go through the entire process of getting “down and dirty” with the primary research and appraising it to influence our practice. Maxi‐EBHC is considerably more demanding in time, but largely more satisfying intellectually.
If we reframe the practice of EBHC as using the family and child values, the best evidence, and our clinical expertise, then we can do it by micro‐methods, midi‐methods or maxi‐methods, and choose the most appropriate approach for the situation we confront.
Acknowledgement
I thank Dr Sharon Straus, Director of the Center for Evidence‐based Medicine, University of Toronto, Toronto, Ontario, Canada.
doi:10.1136/adc.2006.110080
PMCID: PMC2083440
17.  Internet-Based Device-Assisted Remote Monitoring of Cardiovascular Implantable Electronic Devices 
Executive Summary
Objective
The objective of this Medical Advisory Secretariat (MAS) report was to conduct a systematic review of the available published evidence on the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted remote monitoring systems (RMSs) for therapeutic cardiac implantable electronic devices (CIEDs) such as pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. The MAS evidence-based review was performed to support public financing decisions.
Clinical Need: Condition and Target Population
Sudden cardiac death (SCD) is a major cause of fatalities in developed countries. In the United States almost half a million people die of SCD annually, resulting in more deaths than stroke, lung cancer, breast cancer, and AIDS combined. In Canada each year more than 40,000 people die from a cardiovascular related cause; approximately half of these deaths are attributable to SCD.
Most cases of SCD occur in the general population typically in those without a known history of heart disease. Most SCDs are caused by cardiac arrhythmia, an abnormal heart rhythm caused by malfunctions of the heart’s electrical system. Up to half of patients with significant heart failure (HF) also have advanced conduction abnormalities.
Cardiac arrhythmias are managed by a variety of drugs, ablative procedures, and therapeutic CIEDs. The range of CIEDs includes pacemakers (PMs), implantable cardioverter-defibrillators (ICDs), and cardiac resynchronization therapy (CRT) devices. Bradycardia is the main indication for PMs and individuals at high risk for SCD are often treated by ICDs.
Heart failure (HF) is also a significant health problem and is the most frequent cause of hospitalization in those over 65 years of age. Patients with moderate to severe HF may also have cardiac arrhythmias, although the cause may be related more to heart pump or haemodynamic failure. The presence of HF, however, increases the risk of SCD five-fold, regardless of aetiology. Patients with HF who remain highly symptomatic despite optimal drug therapy are sometimes also treated with CRT devices.
With an increasing prevalence of age-related conditions such as chronic HF and the expanding indications for ICD therapy, the rate of ICD placement has been dramatically increasing. The appropriate indications for ICD placement, as well as the rate of ICD placement, are increasingly an issue. In the United States, after the introduction of expanded coverage of ICDs, a national ICD registry was created in 2005 to track these devices. A recent survey based on this national ICD registry reported that 22.5% (25,145) of patients had received a non-evidence based ICD and that these patients experienced significantly higher in-hospital mortality and post-procedural complications.
In addition to the increased ICD device placement and the upfront device costs, there is the need for lifelong follow-up or surveillance, placing a significant burden on patients and device clinics. In 2007, over 1.6 million CIEDs were implanted in Europe and the United States, which translates to over 5.5 million patient encounters per year if the recommended follow-up practices are considered. A safe and effective RMS could potentially improve the efficiency of long-term follow-up of patients and their CIEDs.
Technology
In addition to being therapeutic devices, CIEDs have extensive diagnostic abilities. All CIEDs can be interrogated and reprogrammed during an in-clinic visit using an inductive programming wand. Remote monitoring would allow patients to transmit information recorded in their devices from the comfort of their own homes. Currently most ICD devices also have the potential to be remotely monitored. Remote monitoring (RM) can be used to check system integrity, to alert on arrhythmic episodes, and to potentially replace in-clinic follow-ups and manage disease remotely. They do not currently have the capability of being reprogrammed remotely, although this feature is being tested in pilot settings.
Every RMS is specifically designed by a manufacturer for their cardiac implant devices. For Internet-based device-assisted RMSs, this customization includes details such as web application, multiplatform sensors, custom algorithms, programming information, and types and methods of alerting patients and/or physicians. The addition of peripherals for monitoring weight and pressure or communicating with patients through the onsite communicators also varies by manufacturer. Internet-based device-assisted RMSs for CIEDs are intended to function as a surveillance system rather than an emergency system.
Health care providers therefore need to learn each application, and as more than one application may be used at one site, multiple applications may need to be reviewed for alarms. All RMSs deliver system integrity alerting; however, some systems seem to be better geared to fast arrhythmic alerting, whereas other systems appear to be more intended for remote follow-up or supplemental remote disease management. The different RMSs may therefore have different impacts on workflow organization because of their varying frequency of interrogation and methods of alerts. The integration of these proprietary RM web-based registry systems with hospital-based electronic health record systems has so far not been commonly implemented.
Currently there are 2 general types of RMSs: those that transmit device diagnostic information automatically and without patient assistance to secure Internet-based registry systems, and those that require patient assistance to transmit information. Both systems employ the use of preprogrammed alerts that are either transmitted automatically or at regular scheduled intervals to patients and/or physicians.
The current web applications, programming, and registry systems differ greatly between the manufacturers of transmitting cardiac devices. In Canada there are currently 4 manufacturers—Medtronic Inc., Biotronik, Boston Scientific Corp., and St Jude Medical Inc.—which have regulatory approval for remote transmitting CIEDs. Remote monitoring systems are proprietary to the manufacturer of the implant device. An RMS for one device will not work with another device, and the RMS may not work with all versions of the manufacturer’s devices.
All Internet-based device-assisted RMSs have common components. The implanted device is equipped with a micro-antenna that communicates with a small external device (at bedside or wearable) commonly known as the transmitter. Transmitters are able to interrogate programmed parameters and diagnostic data stored in the patients’ implant device. The information transfer to the communicator can occur at preset time intervals with the participation of the patient (waving a wand over the device) or it can be sent automatically (wirelessly) without their participation. The encrypted data are then uploaded to an Internet-based database on a secure central server. The data processing facilities at the central database, depending on the clinical urgency, can trigger an alert for the physician(s) that can be sent via email, fax, text message, or phone. The details are also posted on the secure website for viewing by the physician (or their delegate) at their convenience.
Research Questions
The research directions and specific research questions for this evidence review were as follows:
To identify the Internet-based device-assisted RMSs available for follow-up of patients with therapeutic CIEDs such as PMs, ICDs, and CRT devices.
To identify the potential risks, operational issues, or organizational issues related to Internet-based device-assisted RM for CIEDs.
To evaluate the safety, acceptability, and effectiveness of Internet-based device-assisted RMSs for CIEDs such as PMs, ICDs, and CRT devices.
To evaluate the safety, effectiveness, and cost-effectiveness of Internet-based device-assisted RMSs for CIEDs compared to usual outpatient in-office monitoring strategies.
To evaluate the resource implications or budget impact of RMSs for CIEDs in Ontario, Canada.
Research Methods
Literature Search
The review included a systematic review of published scientific literature and consultations with experts and manufacturers of all 4 approved RMSs for CIEDs in Canada. Information on CIED cardiac implant clinics was also obtained from Provincial Programs, a division within the Ministry of Health and Long-Term Care with a mandate for cardiac implant specialty care. Various administrative databases and registries were used to outline the current clinical follow-up burden of CIEDs in Ontario. The provincial population-based ICD database developed and maintained by the Institute for Clinical Evaluative Sciences (ICES) was used to review the current follow-up practices with Ontario patients implanted with ICD devices.
Search Strategy
A literature search was performed on September 21, 2010 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from 1950 to September 2010. Search alerts were generated and reviewed for additional relevant literature until December 31, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
published between 1950 and September 2010;
English language full-reports and human studies;
original reports including clinical evaluations of Internet-based device-assisted RMSs for CIEDs in clinical settings;
reports including standardized measurements on outcome events such as technical success, safety, effectiveness, cost, measures of health care utilization, morbidity, mortality, quality of life or patient satisfaction;
randomized controlled trials (RCTs), systematic reviews and meta-analyses, cohort and controlled clinical studies.
Exclusion Criteria
non-systematic reviews, letters, comments and editorials;
reports not involving standardized outcome events;
clinical reports not involving Internet-based device assisted RM systems for CIEDs in clinical settings;
reports involving studies testing or validating algorithms without RM;
studies with small samples (<10 subjects).
Outcomes of Interest
The outcomes of interest included: technical outcomes, emergency department visits, complications, major adverse events, symptoms, hospital admissions, clinic visits (scheduled and/or unscheduled), survival, morbidity (disease progression, stroke, etc.), patient satisfaction, and quality of life.
Summary of Findings
The MAS evidence review was performed to review available evidence on Internet-based device-assisted RMSs for CIEDs published until September 2010. The search identified 6 systematic reviews, 7 randomized controlled trials, and 19 reports for 16 cohort studies—3 of these being registry-based and 4 being multi-centered. The evidence is summarized in the 3 sections that follow.
1. Effectiveness of Remote Monitoring Systems of CIEDs for Cardiac Arrhythmia and Device Functioning
In total, 15 reports on 13 cohort studies involving investigations with 4 different RMSs for CIEDs in cardiology implant clinic groups were identified in the review. The 4 RMSs were: Care Link Network® (Medtronic Inc,, Minneapolis, MN, USA); Home Monitoring® (Biotronic, Berlin, Germany); House Call 11® (St Jude Medical Inc., St Pauls, MN, USA); and a manufacturer-independent RMS. Eight of these reports were with the Home Monitoring® RMS (12,949 patients), 3 were with the Care Link® RMS (167 patients), 1 was with the House Call 11® RMS (124 patients), and 1 was with a manufacturer-independent RMS (44 patients). All of the studies, except for 2 in the United States, (1 with Home Monitoring® and 1 with House Call 11®), were performed in European countries.
The RMSs in the studies were evaluated with different cardiac implant device populations: ICDs only (6 studies), ICD and CRT devices (3 studies), PM and ICD and CRT devices (4 studies), and PMs only (2 studies). The patient populations were predominately male (range, 52%–87%) in all studies, with mean ages ranging from 58 to 76 years. One study population was unique in that RMSs were evaluated for ICDs implanted solely for primary prevention in young patients (mean age, 44 years) with Brugada syndrome, which carries an inherited increased genetic risk for sudden heart attack in young adults.
Most of the cohort studies reported on the feasibility of RMSs in clinical settings with limited follow-up. In the short follow-up periods of the studies, the majority of the events were related to detection of medical events rather than system configuration or device abnormalities. The results of the studies are summarized below:
The interrogation of devices on the web platform, both for continuous and scheduled transmissions, was significantly quicker with remote follow-up, both for nurses and physicians.
In a case-control study focusing on a Brugada population–based registry with patients followed-up remotely, there were significantly fewer outpatient visits and greater detection of inappropriate shocks. One death occurred in the control group not followed remotely and post-mortem analysis indicated early signs of lead failure prior to the event.
Two studies examined the role of RMSs in following ICD leads under regulatory advisory in a European clinical setting and noted:
– Fewer inappropriate shocks were administered in the RM group.
– Urgent in-office interrogations and surgical revisions were performed within 12 days of remote alerts.
– No signs of lead fracture were detected at in-office follow-up; all were detected at remote follow-up.
Only 1 study reported evaluating quality of life in patients followed up remotely at 3 and 6 months; no values were reported.
Patient satisfaction was evaluated in 5 cohort studies, all in short term follow-up: 1 for the Home Monitoring® RMS, 3 for the Care Link® RMS, and 1 for the House Call 11® RMS.
– Patients reported receiving a sense of security from the transmitter, a good relationship with nurses and physicians, positive implications for their health, and satisfaction with RM and organization of services.
– Although patients reported that the system was easy to implement and required less than 10 minutes to transmit information, a variable proportion of patients (range, 9% 39%) reported that they needed the assistance of a caregiver for their transmission.
– The majority of patients would recommend RM to other ICD patients.
– Patients with hearing or other physical or mental conditions hindering the use of the system were excluded from studies, but the frequency of this was not reported.
Physician satisfaction was evaluated in 3 studies, all with the Care Link® RMS:
– Physicians reported an ease of use and high satisfaction with a generally short-term use of the RMS.
– Physicians reported being able to address the problems in unscheduled patient transmissions or physician initiated transmissions remotely, and were able to handle the majority of the troubleshooting calls remotely.
– Both nurses and physicians reported a high level of satisfaction with the web registry system.
2. Effectiveness of Remote Monitoring Systems in Heart Failure Patients for Cardiac Arrhythmia and Heart Failure Episodes
Remote follow-up of HF patients implanted with ICD or CRT devices, generally managed in specialized HF clinics, was evaluated in 3 cohort studies: 1 involved the Home Monitoring® RMS and 2 involved the Care Link® RMS. In these RMSs, in addition to the standard diagnostic features, the cardiac devices continuously assess other variables such as patient activity, mean heart rate, and heart rate variability. Intra-thoracic impedance, a proxy measure for lung fluid overload, was also measured in the Care Link® studies. The overall diagnostic performance of these measures cannot be evaluated, as the information was not reported for patients who did not experience intra-thoracic impedance threshold crossings or did not undergo interventions. The trial results involved descriptive information on transmissions and alerts in patients experiencing high morbidity and hospitalization in the short study periods.
3. Comparative Effectiveness of Remote Monitoring Systems for CIEDs
Seven RCTs were identified evaluating RMSs for CIEDs: 2 were for PMs (1276 patients) and 5 were for ICD/CRT devices (3733 patients). Studies performed in the clinical setting in the United States involved both the Care Link® RMS and the Home Monitoring® RMS, whereas all studies performed in European countries involved only the Home Monitoring® RMS.
3A. Randomized Controlled Trials of Remote Monitoring Systems for Pacemakers
Two trials, both multicenter RCTs, were conducted in different countries with different RMSs and study objectives. The PREFER trial was a large trial (897 patients) performed in the United States examining the ability of Care Link®, an Internet-based remote PM interrogation system, to detect clinically actionable events (CAEs) sooner than the current in-office follow-up supplemented with transtelephonic monitoring transmissions, a limited form of remote device interrogation. The trial results are summarized below:
In the 375-day mean follow-up, 382 patients were identified with at least 1 CAE—111 patients in the control arm and 271 in the remote arm.
The event rate detected per patient for every type of CAE, except for loss of atrial capture, was higher in the remote arm than the control arm.
The median time to first detection of CAEs (4.9 vs. 6.3 months) was significantly shorter in the RMS group compared to the control group (P < 0.0001).
Additionally, only 2% (3/190) of the CAEs in the control arm were detected during a transtelephonic monitoring transmission (the rest were detected at in-office follow-ups), whereas 66% (446/676) of the CAEs were detected during remote interrogation.
The second study, the OEDIPE trial, was a smaller trial (379 patients) performed in France evaluating the ability of the Home Monitoring® RMS to shorten PM post-operative hospitalization while preserving the safety of conventional management of longer hospital stays.
Implementation and operationalization of the RMS was reported to be successful in 91% (346/379) of the patients and represented 8144 transmissions.
In the RM group 6.5% of patients failed to send messages (10 due to improper use of the transmitter, 2 with unmanageable stress). Of the 172 patients transmitting, 108 patients sent a total of 167 warnings during the trial, with a greater proportion of warnings being attributed to medical rather than technical causes.
Forty percent had no warning message transmission and among these, 6 patients experienced a major adverse event and 1 patient experienced a non-major adverse event. Of the 6 patients having a major adverse event, 5 contacted their physician.
The mean medical reaction time was faster in the RM group (6.5 ± 7.6 days vs. 11.4 ± 11.6 days).
The mean duration of hospitalization was significantly shorter (P < 0.001) for the RM group than the control group (3.2 ± 3.2 days vs. 4.8 ± 3.7 days).
Quality of life estimates by the SF-36 questionnaire were similar for the 2 groups at 1-month follow-up.
3B. Randomized Controlled Trials Evaluating Remote Monitoring Systems for ICD or CRT Devices
The 5 studies evaluating the impact of RMSs with ICD/CRT devices were conducted in the United States and in European countries and involved 2 RMSs—Care Link® and Home Monitoring ®. The objectives of the trials varied and 3 of the trials were smaller pilot investigations.
The first of the smaller studies (151 patients) evaluated patient satisfaction, achievement of patient outcomes, and the cost-effectiveness of the Care Link® RMS compared to quarterly in-office device interrogations with 1-year follow-up.
Individual outcomes such as hospitalizations, emergency department visits, and unscheduled clinic visits were not significantly different between the study groups.
Except for a significantly higher detection of atrial fibrillation in the RM group, data on ICD detection and therapy were similar in the study groups.
Health-related quality of life evaluated by the EuroQoL at 6-month or 12-month follow-up was not different between study groups.
Patients were more satisfied with their ICD care in the clinic follow-up group than in the remote follow-up group at 6-month follow-up, but were equally satisfied at 12- month follow-up.
The second small pilot trial (20 patients) examined the impact of RM follow-up with the House Call 11® system on work schedules and cost savings in patients randomized to 2 study arms varying in the degree of remote follow-up.
The total time including device interrogation, transmission time, data analysis, and physician time required was significantly shorter for the RM follow-up group.
The in-clinic waiting time was eliminated for patients in the RM follow-up group.
The physician talk time was significantly reduced in the RM follow-up group (P < 0.05).
The time for the actual device interrogation did not differ in the study groups.
The third small trial (115 patients) examined the impact of RM with the Home Monitoring® system compared to scheduled trimonthly in-clinic visits on the number of unplanned visits, total costs, health-related quality of life (SF-36), and overall mortality.
There was a 63.2% reduction in in-office visits in the RM group.
Hospitalizations or overall mortality (values not stated) were not significantly different between the study groups.
Patient-induced visits were higher in the RM group than the in-clinic follow-up group.
The TRUST Trial
The TRUST trial was a large multicenter RCT conducted at 102 centers in the United States involving the Home Monitoring® RMS for ICD devices for 1450 patients. The primary objectives of the trial were to determine if remote follow-up could be safely substituted for in-office clinic follow-up (3 in-office visits replaced) and still enable earlier physician detection of clinically actionable events.
Adherence to the protocol follow-up schedule was significantly higher in the RM group than the in-office follow-up group (93.5% vs. 88.7%, P < 0.001).
Actionability of trimonthly scheduled checks was low (6.6%) in both study groups. Overall, actionable causes were reprogramming (76.2%), medication changes (24.8%), and lead/system revisions (4%), and these were not different between the 2 study groups.
The overall mean number of in-clinic and hospital visits was significantly lower in the RM group than the in-office follow-up group (2.1 per patient-year vs. 3.8 per patient-year, P < 0.001), representing a 45% visit reduction at 12 months.
The median time from onset of first arrhythmia to physician evaluation was significantly shorter (P < 0.001) in the RM group than in the in-office follow-up group for all arrhythmias (1 day vs. 35.5 days).
The median time to detect clinically asymptomatic arrhythmia events—atrial fibrillation (AF), ventricular fibrillation (VF), ventricular tachycardia (VT), and supra-ventricular tachycardia (SVT)—was also significantly shorter (P < 0.001) in the RM group compared to the in-office follow-up group (1 day vs. 41.5 days) and was significantly quicker for each of the clinical arrhythmia events—AF (5.5 days vs. 40 days), VT (1 day vs. 28 days), VF (1 day vs. 36 days), and SVT (2 days vs. 39 days).
System-related problems occurred infrequently in both groups—in 1.5% of patients (14/908) in the RM group and in 0.7% of patients (3/432) in the in-office follow-up group.
The overall adverse event rate over 12 months was not significantly different between the 2 groups and individual adverse events were also not significantly different between the RM group and the in-office follow-up group: death (3.4% vs. 4.9%), stroke (0.3% vs. 1.2%), and surgical intervention (6.6% vs. 4.9%), respectively.
The 12-month cumulative survival was 96.4% (95% confidence interval [CI], 95.5%–97.6%) in the RM group and 94.2% (95% confidence interval [CI], 91.8%–96.6%) in the in-office follow-up group, and was not significantly different between the 2 groups (P = 0.174).
The CONNECT Trial
The CONNECT trial, another major multicenter RCT, involved the Care Link® RMS for ICD/CRT devices in a15-month follow-up study of 1,997 patients at 133 sites in the United States. The primary objective of the trial was to determine whether automatically transmitted physician alerts decreased the time from the occurrence of clinically relevant events to medical decisions. The trial results are summarized below:
Of the 575 clinical alerts sent in the study, 246 did not trigger an automatic physician alert. Transmission failures were related to technical issues such as the alert not being programmed or not being reset, and/or a variety of patient factors such as not being at home and the monitor not being plugged in or set up.
The overall mean time from the clinically relevant event to the clinical decision was significantly shorter (P < 0.001) by 17.4 days in the remote follow-up group (4.6 days for 172 patients) than the in-office follow-up group (22 days for 145 patients).
– The median time to a clinical decision was shorter in the remote follow-up group than in the in-office follow-up group for an AT/AF burden greater than or equal to 12 hours (3 days vs. 24 days) and a fast VF rate greater than or equal to 120 beats per minute (4 days vs. 23 days).
Although infrequent, similar low numbers of events involving low battery and VF detection/therapy turned off were noted in both groups. More alerts, however, were noted for out-of-range lead impedance in the RM group (18 vs. 6 patients), and the time to detect these critical events was significantly shorter in the RM group (same day vs. 17 days).
Total in-office clinic visits were reduced by 38% from 6.27 visits per patient-year in the in-office follow-up group to 3.29 visits per patient-year in the remote follow-up group.
Health care utilization visits (N = 6,227) that included cardiovascular-related hospitalization, emergency department visits, and unscheduled clinic visits were not significantly higher in the remote follow-up group.
The overall mean length of hospitalization was significantly shorter (P = 0.002) for those in the remote follow-up group (3.3 days vs. 4.0 days) and was shorter both for patients with ICD (3.0 days vs. 3.6 days) and CRT (3.8 days vs. 4.7 days) implants.
The mortality rate between the study arms was not significantly different between the follow-up groups for the ICDs (P = 0.31) or the CRT devices with defribillator (P = 0.46).
Conclusions
There is limited clinical trial information on the effectiveness of RMSs for PMs. However, for RMSs for ICD devices, multiple cohort studies and 2 large multicenter RCTs demonstrated feasibility and significant reductions in in-office clinic follow-ups with RMSs in the first year post implantation. The detection rates of clinically significant events (and asymptomatic events) were higher, and the time to a clinical decision for these events was significantly shorter, in the remote follow-up groups than in the in-office follow-up groups. The earlier detection of clinical events in the remote follow-up groups, however, was not associated with lower morbidity or mortality rates in the 1-year follow-up. The substitution of almost all the first year in-office clinic follow-ups with RM was also not associated with an increased health care utilization such as emergency department visits or hospitalizations.
The follow-up in the trials was generally short-term, up to 1 year, and was a more limited assessment of potential longer term device/lead integrity complications or issues. None of the studies compared the different RMSs, particularly the different RMSs involving patient-scheduled transmissions or automatic transmissions. Patients’ acceptance of and satisfaction with RM were reported to be high, but the impact of RM on patients’ health-related quality of life, particularly the psychological aspects, was not evaluated thoroughly. Patients who are not technologically competent, having hearing or other physical/mental impairments, were identified as potentially disadvantaged with remote surveillance. Cohort studies consistently identified subgroups of patients who preferred in-office follow-up. The evaluation of costs and workflow impact to the health care system were evaluated in European or American clinical settings, and only in a limited way.
Internet-based device-assisted RMSs involve a new approach to monitoring patients, their disease progression, and their CIEDs. Remote monitoring also has the potential to improve the current postmarket surveillance systems of evolving CIEDs and their ongoing hardware and software modifications. At this point, however, there is insufficient information to evaluate the overall impact to the health care system, although the time saving and convenience to patients and physicians associated with a substitution of in-office follow-up by RM is more certain. The broader issues surrounding infrastructure, impacts on existing clinical care systems, and regulatory concerns need to be considered for the implementation of Internet-based RMSs in jurisdictions involving different clinical practices.
PMCID: PMC3377571  PMID: 23074419
18.  64-Slice Computed Tomographic Angiography for the Diagnosis of Intermediate Risk Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of this report is to determine the accuracy of computed tomographic angiography (CTA) compared to the more invasive option of coronary angiography (CA) in the detection of coronary artery disease (CAD) in stable (non-emergent) symptomatic patients.
CT Angiography
CTA is a cardiac imaging test that assesses the presence or absence, as well as the extent, of coronary artery stenosis for the diagnosis of CAD. As such, it is a test of cardiac structure and anatomy, in contrast to the other cardiac imaging modalities that assess cardiac function. It is, however, unclear as to whether cardiac structural features alone, in the absence cardiac function information, are sufficient to determine the presence or absence of intermediate pretest risk of CAD.
CTA technology is changing rapidly with increasing scan speeds and anticipated reductions in radiation exposure. Initial scanners based on 4, 8, 16, 32, and 64 slice machines have been available since the end of 2004. Although 320-slice machines are now available, these are not widely diffused and the existing published evidence is specific to 64-slice scanners. In general, CTA allows for 3-dimensional (3D) viewing of the coronary arteries derived from software algorithms of 2-dimensional (2D) images.
The advantage of CTA over CA, the gold standard for the diagnosis of CAD, is that it is relatively less invasive and may serve as a test in determining which patients are best suited for a CA. CA requires insertion of a catheter through an artery in the arm or leg up to the area being studied, yet both tests involve contrast agents and radiation exposure. Therefore, the identification of patients for whom CTA or CA is more appropriate may help to avoid more invasive tests, treatment delays, and unnecessary radiation exposure. The main advantage of CA, however, is that treatment can be administered in the same session as the test procedure and as such, it’s recommended for patients with a pre-test probability of CAD of ≥80%. The progression to the more invasive CA allows for the diagnosis and treatment in one session without the added radiation exposure from a previous CTA.
The visibility of arteries in CTA images is best in populations with a disease prevalence, or pre-test probabilities of CAD, of 40% to 80%, beyond which patients are considered at high pre-test probability. Visibility decreases with increasing prevalence as arteries become increasingly calcified (coronary artery calcification is based on the Agaston score). Such higher risk patients are not candidates for the less invasive diagnostic procedures and should proceed directly to CA, where treatment can be administered in conjunction with the test itself, while bypassing the radiation exposure from CTA.
CTA requires the addition of an ionated contrast, which can be administered only in patients with sufficient renal function (creatinine levels >30 micromoles/litre) to allow for the clearing of the contrast from the body. In some cases, the contrast is administered in patients with creatinine levels less than 30 micromoles/litre.
A second important criterion for the administration of the CTA is patient heart rate, which should be less than 65 beats/min for the single source CTA machines and less than 80 beats/min for the dual source machines. To decrease heart rates to these levels, beta-blockers are often required. Although the accuracy of these two machines does not differ, the dual source machines can be utilized in a higher proportion of patients than the single source machines for patients with heart beats of up to 80 beats/min. Approximately 10% of patients are considered ineligible for CTA because of this inability to decrease heart rates to the required levels. Additional contra-indications include renal insufficiency as described above and atrial fibrillation, with approximately 10% of intermediate risk patients ineligible for CTA due these contraindications. The duration of the procedure may be between 1 and 1.5 hours, with about 15 minutes for the CTA and the remaining time for the preparation of the patient.
CTA is licensed by Health Canada as a Class III device. Currently, two companies have licenses for 64-slice CT scanners, Toshiba Medical Systems Corporation (License 67604) and Philips Medical Systems (License 67599 and 73260).
Research Questions
How does the accuracy of CTA compare to the more invasive CA in the diagnosis of CAD in symptomatic patients at intermediate risk of the disease?
How does the accuracy for CTA compare to other modalities in the detection of CAD?
Research Methods
Literature Search
A literature search was performed on July 20, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until July 20, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language articles and English or French-language HTAs published from January 1, 2004 to July 20, 2009.
Randomized controlled trials (RCTs), non-randomized clinical trials, systematic reviews and meta-analyses.
Studies of symptomatic patients at intermediate pre-test probability of CAD.
Studies of single source CTA compared to CA for the diagnosis of CAD.
Studies in which sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) could be established. HTAs, SRs, clinical trials, observational studies.
Exclusion Criteria
Non-English studies.
Pediatric populations.
Studies of patients at low or high pre-test probability of CAD.
Studies of unstable patients, e.g., emergency room visits, or a prior diagnosis of CAD.
Studies in patients with non-ischemic heart disease.
Studies in which outcomes were not specific to those of interest in this report.
Studies in which CTA was not compared to CA in a stable population.
Outcomes of Interest)
CAD defined as ≥50% stenosis.
Comparator
Coronary angiography.
Measures of Interest
Sensitivity, specificity;
Negative predictive value (NPV), positive predictive value (PPV);
Area under the curve (AUC) and diagnostic odds ratios (DOR).
Results of Literature Search and Evidence-Based Analysis
The literature search yielded two HTAs, the first published by MAS in April 2005, the other from the Belgian Health Care Knowledge Centre published in 2008, as well as three recent non-randomized clinical studies. The three most significant studies concerning the accuracy of CTA versus CA are the CORE-64 study, the ACCURACY trial, and a prospective, multicenter, multivendor study conducted in the Netherlands. Five additional non-randomized studies were extracted from the Belgian Health Technology Assessment (2008).
To provide summary estimates of sensitivity, specificity, area under the SROC curve (AUC) and diagnostic odds rations (DORs), a meta-analysis of the above-mentioned studies was conducted. Pooled estimates of sensitivity and specificity were 97.7% (95%CI: 95.5% - 99.9%) and 78.8% (95%CI: 70.8% - 86.8%), respectively. These results indicate that the sensitivity of CTA is almost as good as CA, while its specificity is poorer. The diagnostic odds ratio (DOR) was estimated at 157.0 (95%CI: 11.2 - 302.7) and the AUC was found to be 0.94; however, the inability to provide confidence estimates for this estimate decreased its utility as an adequate outcome measure in this review.
This meta-analysis was limited by the significant heterogeneity between studies for both the pooled sensitivity and specificity (heterogeneity Chi-square p=0.000). To minimize these statistical concerns, the analysis was restricted to studies of intermediate risk patients with no previous history of cardiac events. Nevertheless, the underlying prevalence of CAD ranged from 24.8% to 78% between studies, indicating that there was still some variability in the pre-test probabilities of disease within this stable population. The variation in the prevalence of CAD, accompanied with differences in the proportion of calcification, likely affected the specificity directly and the sensitivity indirectly across studies.
In February 2010, the results of the Ontario Multi-detector Computed Tomography Coronary Angiography Study (OMCAS) became available and were thus included in a second meta-analysis of the above studies. The OMCAS was a non-randomized double-blind study conducted in 3 centers in Ontario that was conducted as a result of a MAS review from 2005 requesting an evaluation of the accuracy of 64-slice CTA for CAD detection. Within 10 days of their scheduled CA, all patients received an additional evaluation with CTA. Included in the meta-analysis with the above-mentioned studies are 117 symptomatic patients with intermediate probability of CAD (10% - 90% probability), resulting in a pooled sensitivity of 96.1% (95%CI: 94.0%-98.3%) and pooled specificity of 81.5% (95%CI: 73.0% - 89.9%).
Summary of Findings
CTA is almost as good as CA in detecting true positives but poorer in the rate of false positives. The main value of CTA may be in ruling out significant CAD.
Increased prevalence of CAD decreases study specificity, whereas specificity is increased in the presence of increased arterial calcification even in lower prevalence studies.
Positive CT angiograms may require additional tests such as stress tests or the more invasive CA, partly to identify false positives.
Radiation exposure is an important safety concern that needs to be considered, particularly the cumulative exposures from repeat CTAs.
PMCID: PMC3377576  PMID: 23074388
19.  Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD) 
Executive Summary
In July 2010, the Medical Advisory Secretariat (MAS) began work on a Chronic Obstructive Pulmonary Disease (COPD) evidentiary framework, an evidence-based review of the literature surrounding treatment strategies for patients with COPD. This project emerged from a request by the Health System Strategy Division of the Ministry of Health and Long-Term Care that MAS provide them with an evidentiary platform on the effectiveness and cost-effectiveness of COPD interventions.
After an initial review of health technology assessments and systematic reviews of COPD literature, and consultation with experts, MAS identified the following topics for analysis: vaccinations (influenza and pneumococcal), smoking cessation, multidisciplinary care, pulmonary rehabilitation, long-term oxygen therapy, noninvasive positive pressure ventilation for acute and chronic respiratory failure, hospital-at-home for acute exacerbations of COPD, and telehealth (including telemonitoring and telephone support). Evidence-based analyses were prepared for each of these topics. For each technology, an economic analysis was also completed where appropriate. In addition, a review of the qualitative literature on patient, caregiver, and provider perspectives on living and dying with COPD was conducted, as were reviews of the qualitative literature on each of the technologies included in these analyses.
The Chronic Obstructive Pulmonary Disease Mega-Analysis series is made up of the following reports, which can be publicly accessed at the MAS website at: http://www.hqontario.ca/en/mas/mas_ohtas_mn.html.
Chronic Obstructive Pulmonary Disease (COPD) Evidentiary Framework
Influenza and Pneumococcal Vaccinations for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Smoking Cessation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Community-Based Multidisciplinary Care for Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Pulmonary Rehabilitation for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Long-term Oxygen Therapy for Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Acute Respiratory Failure Patients With Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Noninvasive Positive Pressure Ventilation for Chronic Respiratory Failure Patients With Stable Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Hospital-at-Home Programs for Patients With Acute Exacerbations of Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Home Telehealth for Patients with Chronic Obstructive Pulmonary Disease (COPD): An Evidence-Based Analysis
Cost-Effectiveness of Interventions for Chronic Obstructive Pulmonary Disease Using an Ontario Policy Model
Experiences of Living and Dying With COPD: A Systematic Review and Synthesis of the Qualitative Empirical Literature
For more information on the qualitative review, please contact Mita Giacomini at: http://fhs.mcmaster.ca/ceb/faculty_member_giacomini.htm.
For more information on the economic analysis, please visit the PATH website: http://www.path-hta.ca/About-Us/Contact-Us.aspx.
The Toronto Health Economics and Technology Assessment (THETA) collaborative has produced an associated report on patient preference for mechanical ventilation. For more information, please visit the THETA website: http://theta.utoronto.ca/static/contact.
Objective
The objective of this analysis was to compare hospital-at-home care with inpatient hospital care for patients with acute exacerbations of chronic obstructive pulmonary disease (COPD) who present to the emergency department (ED).
Clinical Need: Condition and Target Population
Acute Exacerbations of Chronic Obstructive Pulmonary Disease
Chronic obstructive pulmonary disease is a disease state characterized by airflow limitation that is not fully reversible. This airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. The natural history of COPD involves periods of acute-onset worsening of symptoms, particularly increased breathlessness, cough, and/or sputum, that go beyond normal day-to-day variations; these are known as acute exacerbations.
Two-thirds of COPD exacerbations are caused by an infection of the tracheobronchial tree or by air pollution; the cause in the remaining cases is unknown. On average, patients with moderate to severe COPD experience 2 or 3 exacerbations each year.
Exacerbations have an important impact on patients and on the health care system. For the patient, exacerbations result in decreased quality of life, potentially permanent losses of lung function, and an increased risk of mortality. For the health care system, exacerbations of COPD are a leading cause of ED visits and hospitalizations, particularly in winter.
Technology
Hospital-at-home programs offer an alternative for patients who present to the ED with an exacerbation of COPD and require hospital admission for their treatment. Hospital-at-home programs provide patients with visits in their home by medical professionals (typically specialist nurses) who monitor the patients, alter patients’ treatment plans if needed, and in some programs, provide additional care such as pulmonary rehabilitation, patient and caregiver education, and smoking cessation counselling.
There are 2 types of hospital-at-home programs: admission avoidance and early discharge hospital-at-home. In the former, admission avoidance hospital-at-home, after patients are assessed in the ED, they are prescribed the necessary medications and additional care needed (e.g., oxygen therapy) and then sent home where they receive regular visits from a medical professional. In early discharge hospital-at-home, after being assessed in the ED, patients are admitted to the hospital where they receive the initial phase of their treatment. These patients are discharged into a hospital-at-home program before the exacerbation has resolved. In both cases, once the exacerbation has resolved, the patient is discharged from the hospital-at-home program and no longer receives visits in his/her home.
In the models that exist to date, hospital-at-home programs differ from other home care programs because they deal with higher acuity patients who require higher acuity care, and because hospitals retain the medical and legal responsibility for patients. Furthermore, patients requiring home care services may require such services for long periods of time or indefinitely, whereas patients in hospital-at-home programs require and receive the services for a short period of time only.
Hospital-at-home care is not appropriate for all patients with acute exacerbations of COPD. Ineligible patients include: those with mild exacerbations that can be managed without admission to hospital; those who require admission to hospital; and those who cannot be safely treated in a hospital-at-home program either for medical reasons and/or because of a lack of, or poor, social support at home.
The proposed possible benefits of hospital-at-home for treatment of exacerbations of COPD include: decreased utilization of health care resources by avoiding hospital admission and/or reducing length of stay in hospital; decreased costs; increased health-related quality of life for patients and caregivers when treated at home; and reduced risk of hospital-acquired infections in this susceptible patient population.
Ontario Context
No hospital-at-home programs for the treatment of acute exacerbations of COPD were identified in Ontario. Patients requiring acute care for their exacerbations are treated in hospitals.
Research Question
What is the effectiveness, cost-effectiveness, and safety of hospital-at-home care compared with inpatient hospital care of acute exacerbations of COPD?
Research Methods
Literature Search
Search Strategy
A literature search was performed on August 5, 2010, using OVID MEDLINE, OVID MEDLINE In-Process and Other Non-Indexed Citations, OVID EMBASE, EBSCO Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Wiley Cochrane Library, and the Centre for Reviews and Dissemination database for studies published from January 1, 1990, to August 5, 2010. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists and health technology assessment websites were also examined for any additional relevant studies not identified through the systematic search.
Inclusion Criteria
English language full-text reports;
health technology assessments, systematic reviews, meta-analyses, and randomized controlled trials (RCTs);
studies performed exclusively in patients with a diagnosis of COPD or studies including patients with COPD as well as patients with other conditions, if results are reported for COPD patients separately;
studies performed in patients with acute exacerbations of COPD who present to the ED;
studies published between January 1, 1990, and August 5, 2010;
studies comparing hospital-at-home and inpatient hospital care for patients with acute exacerbations of COPD;
studies that include at least 1 of the outcomes of interest (listed below).
Cochrane Collaboration reviews have defined hospital-at-home programs as those that provide patients with active treatment for their acute exacerbation in their home by medical professionals for a limited period of time (in this case, until the resolution of the exacerbation). If a hospital-at-home program had not been available, these patients would have been admitted to hospital for their treatment.
Exclusion Criteria
< 18 years of age
animal studies
duplicate publications
grey literature
Outcomes of Interest
Patient/clinical outcomes
mortality
lung function (forced expiratory volume in 1 second)
health-related quality of life
patient or caregiver preference
patient or caregiver satisfaction with care
complications
Health system outcomes
hospital readmissions
length of stay in hospital and hospital-at-home
ED visits
transfer to long-term care
days to readmission
eligibility for hospital-at-home
Statistical Methods
When possible, results were pooled using Review Manager 5 Version 5.1; otherwise, results were summarized descriptively. Data from RCTs were analyzed using intention-to-treat protocols. In addition, a sensitivity analysis was done assigning all missing data/withdrawals to the event. P values less than 0.05 were considered significant. A priori subgroup analyses were planned for the acuity of hospital-at-home program, type of hospital-at-home program (early discharge or admission avoidance), and severity of the patients’ COPD. Additional subgroup analyses were conducted as needed based on the identified literature. Post hoc sample size calculations were performed using STATA 10.1.
Quality of Evidence
The quality of each included study was assessed, taking into consideration allocation concealment, randomization, blinding, power/sample size, withdrawals/dropouts, and intention-to-treat analyses.
The quality of the body of evidence was assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
Fourteen studies met the inclusion criteria and were included in this review: 1 health technology assessment, 5 systematic reviews, and 7 RCTs.
The following conclusions are based on low to very low quality of evidence. The reviewed evidence was based on RCTs that were inadequately powered to observe differences between hospital-at-home and inpatient hospital care for most outcomes, so there is a strong possibility of type II error. Given the low to very low quality of evidence, these conclusions must be considered with caution.
Approximately 21% to 37% of patients with acute exacerbations of COPD who present to the ED may be eligible for hospital-at-home care.
Of the patients who are eligible for care, some may refuse to participate in hospital-at-home care.
Eligibility for hospital-at-home care may be increased depending on the design of the hospital-at-home program, such as the size of the geographical service area for hospital-at-home and the hours of operation for patient assessment and entry into hospital-at-home.
Hospital-at-home care for acute exacerbations of COPD was associated with a nonsignificant reduction in the risk of mortality and hospital readmissions compared with inpatient hospital care during 2- to 6-month follow-up.
Limited, very low quality evidence suggests that hospital readmissions are delayed in patients who received hospital-at-home care compared with those who received inpatient hospital care (mean additional days before readmission comparing hospital-at-home to inpatient hospital care ranged from 4 to 38 days).
There is insufficient evidence to determine whether hospital-at-home care, compared with inpatient hospital care, is associated with improved lung function.
The majority of studies did not find significant differences between hospital-at-home and inpatient hospital care for a variety of health-related quality of life measures at follow-up. However, follow-up may have been too late to observe an impact of hospital-at-home care on quality of life.
A conclusion about the impact of hospital-at-home care on length of stay for the initial exacerbation (defined as days in hospital or days in hospital plus hospital-at-home care for inpatient hospital and hospital-at-home, respectively) could not be determined because of limited and inconsistent evidence.
Patient and caregiver satisfaction with care is high for both hospital-at-home and inpatient hospital care.
PMCID: PMC3384361  PMID: 23074420
20.  Cardiovascular and Renal Outcomes of Renin–Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses 
PLoS Medicine  2016;13(3):e1001971.
Background
Medications aimed at inhibiting the renin–angiotensin system (RAS) have been used extensively for preventing cardiovascular and renal complications in patients with diabetes, but data that compare their clinical effectiveness are limited. We aimed to compare the effects of classes of RAS blockers on cardiovascular and renal outcomes in adults with diabetes.
Methods and Findings
Eligible trials were identified by electronic searches in PubMed/MEDLINE and the Cochrane Database of Systematic Reviews (1 January 2004 to 17 July 2014). Interventions of interest were angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and direct renin (DR) inhibitors. The primary endpoints were cardiovascular mortality, myocardial infarction, and stroke—singly and as a composite endpoint, major cardiovascular outcome—and end-stage renal disease [ESRD], doubling of serum creatinine, and all-cause mortality—singly and as a composite endpoint, progression of renal disease. Secondary endpoints were angina pectoris and hospitalization for heart failure. In all, 71 trials (103,120 participants), with a total of 14 different regimens, were pooled using network meta-analyses. When compared with ACE inhibitor, no other RAS blocker used in monotherapy and/or combination was associated with a significant reduction in major cardiovascular outcomes: ARB (odds ratio [OR] 1.02; 95% credible interval [CrI] 0.90–1.18), ACE inhibitor plus ARB (0.97; 95% CrI 0.79–1.19), DR inhibitor plus ACE inhibitor (1.32; 95% CrI 0.96–1.81), and DR inhibitor plus ARB (1.00; 95% CrI 0.73–1.38). For the risk of progression of renal disease, no significant differences were detected between ACE inhibitor and each of the remaining therapies: ARB (OR 1.10; 95% CrI 0.90–1.40), ACE inhibitor plus ARB (0.97; 95% CrI 0.72–1.29), DR inhibitor plus ACE inhibitor (0.99; 95% CrI 0.65–1.57), and DR inhibitor plus ARB (1.18; 95% CrI 0.78–1.84). No significant differences were showed between ACE inhibitors and ARBs with respect to all-cause mortality, cardiovascular mortality, myocardial infarction, stroke, angina pectoris, hospitalization for heart failure, ESRD, or doubling serum creatinine. Findings were limited by the clinical and methodological heterogeneity of the included studies. Potential inconsistency was identified in network meta-analyses of stroke and angina pectoris, limiting the conclusiveness of findings for these single endpoints.
Conclusions
In adults with diabetes, comparisons of different RAS blockers showed similar effects of ACE inhibitors and ARBs on major cardiovascular and renal outcomes. Compared with monotherapies, the combination of an ACE inhibitor and an ARB failed to provide significant benefits on major outcomes. Clinicians should discuss the balance between benefits, costs, and potential harms with individual diabetes patients before starting treatment.
Review registration
PROSPERO CRD42014014404
In a systematic review with network meta-analyses, Ferrán Catalá-López and colleagues synthesize published and unpublished data from randomized controlled trials of renin-angiotensin system inhibitors.
Editors' Summary
Background
Chronic high blood pressure can damage blood vessels, heart, and kidneys, and cause cardiovascular and kidney (or renal) disease. Diabetes increases the risk for high blood pressure. An estimated two-thirds of adults with diabetes have high blood pressure or take blood-pressure-reducing drugs (also called antihypertensives). Because diabetes itself increases the risk for heart and kidney diseases, controlling blood pressure is important. Several of the drugs commonly prescribed to patients with diabetes target the renin–angiotensin system (RAS), a hormone system that regulates blood pressure and fluid balance. When renal blood flow is low, kidney cells produce renin and secrete it into the blood stream. Renin in the blood generates a protein called angiotensin I. The angiotensin-converting enzyme (ACE) in the lungs subsequently converts angiotensin I to angiotensin II, and angiotensin II docks with its partner, the angiotensin receptor. This then leads to a signaling cascade that causes blood vessels to constrict and the kidneys to secrete water and salt into the blood, resulting in increased blood pressure.
Drugs that interrupt different steps in the cascade can lower blood pressure and thereby prevent cardiovascular and renal disease. In addition to their blood-pressure-lowering effects, some RAS blockers have also been shown to protect heart and kidney function through other mechanisms. RAS blockers fall into three main classes: ACE inhibitors block the conversion of angiotensin I into angiotensin II, angiotensin receptor blockers (ARBs) prevent angiotensin II from activating the angiotensin receptor, and direct renin inhibitors inhibit the production of angiotensin I.
Why Was This Study Done?
As many adults with diabetes are prescribed RAS blockers and likely need to take them or related drugs for the rest of their lives, the question of which drug (or drug combination) has the best results and the least side effects is important. Data from many randomized controlled trials (RCTs, which are the most rigorous clinical tests) have generated results that address this question. Their combined analysis, however, is complicated because the trials often don’t compare all treatments directly, don’t use the exact same treatments in patients with the exact same conditions, or don’t measure the exact same outcomes. Nonetheless, scientists have developed methods to analyze such complex data, including a method called network meta-analysis, which helps to integrate and synthesize diverse results to determine the relative merits of multiple treatments. Here the researchers apply network meta-analysis to all available data from RCTs in which adults with diabetes were given RAS blockers, alone or in combination with other high blood pressure treatments, and that measured cardiovascular or renal outcomes.
What Did the Researchers Do and Find?
The researchers started with a systematic search of the medical literature for RCTs that tested RAS blockers alone or in combination in adults with diabetes. They also contacted the sponsors of many studies to find out whether they had additional data that were not included in the published reports. They included all trials that had at least 100 participants, followed the participants for at least 12 months, and reported cardiovascular or renal outcomes. In all, 71 trials that tested a total of 14 different treatment regimens in 103,120 participants met these criteria. With network meta-analysis, the researchers were able to summarize the results of all these trials in a meaningful way. They did this by integrating direct comparisons of RAS blockers within the same trial (where those were available) with indirect comparisons across all trials. The primary endpoints in their analysis were major cardiovascular outcome (a composite of cardiovascular mortality, nonfatal heart attack, and nonfatal stroke) and progression of renal disease (a composite of end-stage renal disease, doubling of serum creatinine [a marker of reduced kidney function], and all-cause mortality). They also analyzed the individual cardiovascular or renal outcomes separately, but these results carried more uncertainty because fewer patients had the individual, compared with the combined, outcomes.
The researchers found no significant differences in the risk of major cardiovascular outcome between ACE inhibitors and either ARBs or a combination of an ACE inhibitor plus an ARB. Similarly, for the risk of progression of renal disease, no significant differences were detected between ACE inhibitors and any of the remaining therapies, such as ARBs or a combination of an ACE inhibitor plus an ARB. They also found that no RAS blocker strategy was superior to ACE inhibitors with respect to all-cause mortality, cardiovascular mortality, heart attacks, strokes, end-stage renal disease, or doubling of serum creatinine. Overall, any single ACE inhibitor or ARB was equally effective as any other, and just as effective as any drug combination.
What Do These Findings Mean?
The findings reinforce North American and European guidelines that recommend ACE inhibitors and ARBs for antihypertensive therapy in patients with diabetes. The fact that combinations of two drugs had outcomes no better than those of a single ACE inhibitor or ARB—together with results from other studies that reported increased adverse effects in patients who took drug combinations—cautions against the use of combination therapy. The findings also contradict earlier reports suggesting that ARBs may increase the risk of cardiovascular outcomes. There were not enough data comparing direct renin inhibitors (a drug class that was developed more recently and therefore has been studied less) with ACE inhibitors or ARBs to allow strong conclusions; additional research might therefore be warranted.
The analyses here did not consider the costs of any particular drug, or any side effects that were not relevant to the outcomes measured. These factors, together with the results here and a patient’s specific situation, should be taken into account when doctors and their patients discuss and decide appropriate treatments.
Additional Information
This list of resources contains links that can be accessed when viewing the PDF on a device or via the online version of the article at http://dx.doi.org/10.1371/journal.pmed.1001971.
The MedlinePlus has links to information on diabetes
The American Diabetes Association provides information on kidney disease, heart disease, and high blood pressure
The European Society of Cardiology has guidelines on diabetes, heart disease, and high blood pressure
The UK National Institute for Health and Care Excellence has guidelines on renin–angiotensin system drugs
doi:10.1371/journal.pmed.1001971
PMCID: PMC4783064  PMID: 26954482
21.  Collagen Cross-Linking Using Riboflavin and Ultraviolet-A for Corneal Thinning Disorders 
Executive Summary
Objective
The main objectives for this evidence-based analysis were to determine the safety and effectiveness of photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A radiation, referred to as CXL, for the management of corneal thinning disease conditions. The comparative safety and effectiveness of corneal cross-linking with other minimally invasive treatments such as intrastromal corneal rings was also reviewed. The Medical Advisory Secretariat (MAS) evidence-based analysis was performed to support public financing decisions.
Subject of the Evidence-Based Analysis
The primary treatment objective for corneal cross-linking is to increase the strength of the corneal stroma, thereby stabilizing the underlying disease process. At the present time, it is the only procedure that treats the underlying disease condition. The proposed advantages for corneal cross-linking are that the procedure is minimally invasive, safe and effective, and it can potentially delay or defer the need for a corneal transplant. In addition, corneal cross-linking does not adversely affect subsequent surgical approaches, if they are necessary, or interfere with corneal transplants. The evidence for these claims for corneal cross-linking in the management of corneal thinning disorders such as keratoconus will be the focus of this review.
The specific research questions for the evidence review were as follows:
Technical: How technically demanding is corneal cross-linking and what are the operative risks?
Safety: What is known about the broader safety profile of corneal cross-linking?
Effectiveness - Corneal Surface Topographic Affects:
What are the corneal surface remodeling effects of corneal cross-linking?
Do these changes interfere with subsequent interventions, particularly corneal transplant known as penetrating keratoplasty (PKP)?
Effectiveness -Visual Acuity:
What impacts does the remodeling have on visual acuity?
Are these impacts predictable, stable, adjustable and durable?
Effectiveness - Refractive Outcomes: What impact does remodeling have on refractive outcomes?
Effectiveness - Visual Quality (Symptoms): What impact does corneal cross-linking have on vision quality such as contrast vision, and decreased visual symptoms (halos, fluctuating vision)?
Effectiveness - Contact lens tolerance: To what extent does contact lens intolerance improve after corneal cross-linking?
Vision-Related QOL: What is the impact of corneal cross-linking on functional visual rehabilitation and quality of life?
Patient satisfaction: Are patients satisfied with their vision following the procedure?
Disease Process:
What impact does corneal cross-linking have on the underling corneal thinning disease process?
Does corneal cross-linking delay or defer the need for a corneal transplant?
What is the comparative safety and effectiveness of corneal cross-linking compared with other minimally invasive treatments for corneal ectasia such as intrastromal corneal rings?
Clinical Need: Target Population and Condition
Corneal ectasia (thinning) disorders represent a range of disorders involving either primary disease conditions, such as keratoconus (KC) and pellucid marginal corneal degeneration, or secondary iatrogenic conditions, such as corneal thinning occurring after laser in situ keratomileusis (LASIK) refractive surgery.
Corneal thinning is a disease that occurs when the normally round dome-shaped cornea progressively thins causing a cone-like bulge or forward protrusion in response to the normal pressure of the eye. The thinning occurs primarily in the stroma layers and is believed to be a breakdown in the collagen process. This bulging can lead to irregular astigmatism or shape of the cornea. Because the anterior part of the cornea is responsible for most of the focusing of the light on the retina, this can then result in loss of visual acuity. The reduced visual acuity can make even simple daily tasks, such as driving, watching television or reading, difficult to perform.
Keratoconus is the most common form of corneal thinning disorder and involves a noninflammatory chronic disease process of progressive corneal thinning. Although the specific cause for the biomechanical alterations in the corneal stroma is unknown, there is a growing body of evidence suggesting that genetic factors may play an important role. Keratoconus is a rare disease (< 0.05% of the population) and is unique among chronic eye diseases because it has an early onset, with a median age of 25 years. Disease management for this condition follows a step-wise approach depending on disease severity. Contact lenses are the primary treatment of choice when there is irregular astigmatism associated with the disease. Patients are referred for corneal transplants as a last option when they can no longer tolerate contact lenses or when lenses no longer provide adequate vision.
Keratoconus is one of the leading indications for corneal transplants and has been so for the last 3 decades. Despite the high success rate of corneal transplants (up to 20 years) there are reasons to defer it as long as possible. Patients with keratoconus are generally young and a longer-term graft survival of at least 30 or 40 years may be necessary. The surgery itself involves lengthy time off work and postsurgery, while potential complications include long-term steroid use, secondary cataracts, and glaucoma. After a corneal transplant, keratoconus may recur resulting in a need for subsequent interventions. Residual refractive errors and astigmatism can remain challenges after transplantation, and high refractive surgery and regraft rates in KC patients have been reported. Visual rehabilitation or recovery of visual acuity after transplant may be slow and/or unsatisfactory to patients.
Description of Technology/Therapy
Corneal cross-linking involves the use of riboflavin (vitamin B2) and ultraviolet-A (UVA) radiation. A UVA irradiation device known as the CXL® device (license number 77989) by ACCUTECH Medical Technologies Inc. has been licensed by Health Canada as a Class II device since September 19, 2008. An illumination device that emits homogeneous UVA, in combination with any generic form of riboflavin, is licensed by Health Canada for the indication to slow or stop the progression of corneal thinning caused by progressive keratectasia, iatrogenic keratectasia after laser-assisted in situ keratomileusis (LASIK) and pellucid marginal degeneration. The same device is named the UV-X® device by IROCMedical, with approvals in Argentina, the European Union and Australia.
UVA devices all use light emitting diodes to generate UVA at a wavelength of 360-380 microns but vary in the number of diodes (5 to 25), focusing systems, working distance, beam diameter, beam uniformity and extent to which the operator can vary the parameters. In Ontario, CXL is currently offered at over 15 private eye clinics by refractive surgeons and ophthalmologists.
The treatment is an outpatient procedure generally performed with topical anesthesia. The treatment consists of several well defined procedures. The epithelial cell layer is first removed, often using a blunt spatula in a 9.0 mm diameter under sterile conditions. This step is followed by the application of topical 0.1% riboflavin (vitamin B2) solution every 3 to 5 minutes for 25 minutes to ensure that the corneal stroma is fully penetrated. A solid-state UVA light source with a wavelength of 370 nm (maximum absorption of riboflavin) and an irradiance of 3 mW/cm2 is used to irradiate the central cornea. Following treatment, a soft bandage lens is applied and prescriptions are given for oral pain medications, preservative-free tears, anti-inflammatory drops (preferably not nonsteroidal anti-inflammatory drugs, or NSAIDs) and antibiotic eye drops. Patients are recalled 1 week following the procedure to evaluate re-epithelialization and they are followed-up subsequently.
Evidence-Based Analysis Methods
A literature search was conducted on photochemical corneal collagen cross-linking with riboflavin (vitamin B2) and ultraviolet-A for the management of corneal thinning disorders using a search strategy with appropriate keywords and subject headings for CXL for literature published up until April 17, 2011. The literature search for this Health Technology Assessment (HTA) review was performed using the Cochrane Library, the Emergency Care Research Institute (ECRI) and the Centre for Reviews and Dissemination. The websites of several other health technology agencies were also reviewed, including the Canadian Agency for Drugs and Technologies in Health (CADTH) and the United Kingdom’s National Institute for Clinical Excellence (NICE). The databases searched included OVID MEDLINE, MEDLINE IN-Process and other Non-Indexed Citations such as EMBASE.
As the evidence review included an intervention for a rare condition, case series and case reports, particularly for complications and adverse events, were reviewed. A total of 316 citations were identified and all abstracts were reviewed by a single reviewer for eligibility. For those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search.
Inclusion Criteria
English-language reports and human studies
patients with any corneal thinning disorder
reports with CXL procedures used alone or in conjunction with other interventions
original reports with defined study methodology
reports including standardized measurements on outcome events such as technical success, safety effectiveness, durability, vision quality of life or patient satisfaction
systematic reviews, meta-analyses, randomized controlled trials, observational studies, retrospective analyses, case series, or case reports for complications and adverse events
Exclusion Criteria
nonsystematic reviews, letters, comments and editorials
reports not involving outcome events such as safety, effectiveness, durability, vision quality or patient satisfaction following an intervention with corneal implants
reports not involving corneal thinning disorders and an intervention involving CXL
Summary of Evidence Findings
In the Medical Advisory Secretariat evidence review on corneal cross-linking, 65 reports (16 case reports) involving 1403 patients were identified on the use of CXL for managing corneal thinning disorders. The reports were summarized according to their primary clinical indication, whether or not secondary interventions were used in conjunction with CXL (referred to as CXL-Plus) and whether or not it was a safety-related report.
The safety review was based on information from the cohort studies evaluating effectiveness, clinical studies evaluating safety, treatment response or recovery, and published case reports of complications. Complications, such as infection and noninfectious keratitis (inflammatory response), reported in case reports, generally occurred in the first week and were successfully treated with topical antibiotics and steroids. Other complications, such as the cytotoxic effects on the targeted corneal stroma, occurred as side effects of the photo-oxidative process generated by riboflavin and ultraviolet-A and were usually reversible.
The reports on treatment effectiveness involved 15 pre-post longitudinal cohort follow-up studies ranging from follow-up of patients’ treated eye only, follow-up in both the treated and untreated fellow-eye; and follow-up in the treated eye only and a control group not receiving treatment. One study was a 3-arm randomized control study (RCT) involving 2 comparators: one comparator was a sham treatment in which one eye was treated with riboflavin only; and the other comparator was the untreated fellow-eye. The outcomes reported across the studies involved statistically significant and clinically relevant improvements in corneal topography and refraction after CXL. In addition, improvements in treated eyes were accompanied by worsening outcomes in the untreated fellow-eyes. Improvements in corneal topography reported at 6 months were maintained at 1- and 2-year follow-up. Visual acuity, although not always improved, was infrequently reported as vision loss. Additional procedures such as the use of intrastromal corneal ring segments, intraocular lenses and refractive surgical practices were reported to result in additional improvements in topography and visual acuity after CXL.
Considerations for Ontario Health System
The total costs of providing CXL therapy to keratoconus patients in Ontario was calculated based on estimated physician, clinic, and medication costs. The total cost per patient was approximately $1,036 for the treatment of one eye, and $1,751 for the treatment of both eyes. The prevalence of keratoconus was estimated at 4,047 patients in FY2011, with an anticipated annual incidence (new cases) of about 148 cases. After distributing the costs of CXL therapy for the FY2011 prevalent keratoconus population over the next 3 years, the estimated average annual cost was approximately $2.1 million, of which about $1.3 million would be physician costs specifically.
Conclusion
Corneal cross-linking effectively stabilizes the underlying disease, and in some cases reverses disease progression as measured by key corneal topographic measures. The affects of CXL on visual acuity are less predictable and the use of adjunct interventions with CXL, such as intrastromal corneal ring segments, refractive surgery, and intraocular lens implants are increasingly employed to both stabilize disease and restore visual acuity. Although the use of adjunct interventions have been shown to result in additional clinical benefit, the order, timing, and risks of performing adjunctive interventions have not been well established.
Although there is potential for serious adverse events with corneal UVA irradiation and photochemical reactions, there have been few reported complications. Those that have occurred tended to be related to side effects of the induced photochemical reactions and were generally reversible. However, to ensure that there are minimal complications with the use of CXL and irradiation, strict adherence to defined CXL procedural protocols is essential.
Keywords
Keratoconus, corneal cross-linking, corneal topography, corneal transplant, visual acuity, refractive error.
PMCID: PMC3377552  PMID: 23074417
22.  Limbal Stem Cell Transplantation 
Executive Summary
Objective
The objective of this analysis is to systematically review limbal stem cell transplantation (LSCT) for the treatment of patients with limbal stem cell deficiency (LSCD). This evidence-based analysis reviews LSCT as a primary treatment for nonpterygium LSCD conditions, and LSCT as an adjuvant therapy to excision for the treatment of pterygium.
Background
Clinical Need: Condition and Target Population
The outer surface of the eye is covered by 2 distinct cell layers: the corneal epithelial layer that overlies the cornea, and the conjunctival epithelial layer that overlies the sclera. These cell types are separated by a transitional zone known as the limbus. The corneal epithelial cells are renewed every 3 to 10 days by a population of stem cells located in the limbus.
Nonpterygium Limbal Stem Cell Deficiency
When the limbal stem cells are depleted or destroyed, LSCD develops. In LSCD, the conjunctival epithelium migrates onto the cornea (a process called conjunctivalization), resulting in a thickened, irregular, unstable corneal surface that is prone to defects, ulceration, corneal scarring, vascularization, and opacity. Patients experience symptoms including severe irritation, discomfort, photophobia, tearing, blepharospasm, chronic inflammation and redness, and severely decreased vision.
Depending on the degree of limbal stem cell loss, LSCD may be total (diffuse) or partial (local). In total LSCD, the limbal stem cell population is completed destroyed and conjunctival epithelium covers the entire cornea. In partial LSCD, some areas of the limbus are unharmed, and the corresponding areas on the cornea maintain phenotypically normal corneal epithelium.
Confirmation of the presence of conjunctivalization is necessary for LSCD diagnosis as the other characteristics and symptoms are nonspecific and indicate a variety of diseases. The definitive test for LSCD is impression cytology, which detects the presence of conjunctival epithelium and its goblet cells on the cornea. However, in the opinion of a corneal expert, diagnosis is often based on clinical assessment, and in the expert’s opinion, it is unclear whether impression cytology is more accurate and reliable than clinical assessment, especially for patients with severe LSCD.
The incidence of LSCD is not well understood. A variety of underlying disorders are associated with LSCD including chemical or thermal injuries, ultraviolet and ionizing radiation, Stevens-Johnson syndrome, multiple surgeries or cryotherapies, contact lens wear, extensive microbial infection, advanced ocular cicatricial pemphigoid, and aniridia. In addition, some LSCD cases are idiopathic. These conditions are uncommon (e.g., the prevalence of aniridia ranges from 1 in 40,000 to 1 in 100,000 people).
Pterygium
Pterygium is a wing-shaped fibrovascular tissue growth from the conjunctiva onto the cornea. Pterygium is the result of partial LSCD caused by localized ultraviolet damage to limbal stem cells. As the pterygium invades the cornea, it may cause irregular astigmatism, loss of visual acuity, chronic irritation, recurrent inflammation, double vision, and impaired ocular motility.
Pterygium occurs worldwide. Incidence and prevalence rates are highest in the “pterygium belt,” which ranges from 30 degrees north to 30 degrees south of the equator, and lower prevalence rates are found at latitudes greater than 40 degrees. The prevalence of pterygium for Caucasians residing in urban, temperate climates is estimated at 1.2%.
Existing Treatments Other Than Technology Being Reviewed
Nonpterygium Limbal Stem Cell Deficiency
In total LSCD, a patient’s limbal stem cells are completely depleted, so any successful treatment must include new stem cells. Autologous oral mucosal epithelium transplantation has been proposed as an alternative to LSCT. However, this procedure is investigational, and there is very limited level 4c evidence1 to support this technique (fewer than 20 eyes examined in 4 case series and 1 case report).
For patients with partial LSCD, treatment may not be necessary if their visual axis is not affected. However, if the visual axis is conjunctivalized, several disease management options exist including repeated mechanical debridement of the abnormal epithelium; intensive, nonpreserved lubrication; bandage contact lenses; autologous serum eye drops; other investigational medical treatments; and transplantation of an amniotic membrane inlay. However, these are all disease management treatments; LSCT is the only curative option.
Pterygium
The primary treatment for pterygium is surgical excision. However, recurrence is a common problem after excision using the bare sclera technique: reported recurrence rates range from 24% to 89%. Thus, a variety of adjuvant therapies have been used to reduce the risk of pterygium recurrence including LSCT, amniotic membrane transplantation (AMT), conjunctival autologous (CAU) transplantation, and mitomycin C (MMC, an antimetabolite drug).
New Technology Being Reviewed
To successfully treat LSCD, the limbal stem cell population must be repopulated. To achieve this, 4 LSCT procedures have been developed: conjunctival-limbal autologous (CLAU) transplantation; living-related conjunctival-limbal allogeneic (lr-CLAL) transplantation; keratolimbal allogeneic (KLAL) transplantation; and ex vivo expansion of limbal stem cells transplantation. Since the ex vivo expansion of limbal stem cells transplantation procedure is considered experimental, it has been excluded from the systematic review. These procedures vary by the source of donor cells and the amount of limbal tissue used. For CLAU transplants, limbal stem cells are obtained from the patient’s healthy eye. For lr-CLAL and KLAL transplants, stem cells are obtained from living-related and cadaveric donor eyes, respectively.
In CLAU and lr-CLAL transplants, 2 to 4 limbal grafts are removed from the superior and inferior limbus of the donor eye. In KLAL transplants, the entire limbus from the donor eye is used.
The recipient eye is prepared by removing the abnormal conjunctival and scar tissue. An incision is made into the conjunctival tissue into which the graft is placed, and the graft is then secured to the neighbouring limbal and scleral tissue with sutures. Some LSCT protocols include concurrent transplantation of an amniotic membrane onto the cornea.
Regulatory Status
Health Canada does not require premarket licensure for stem cells. However, they are subject to Health Canada’s clinical trial regulations until the procedure is considered accepted transplantation practice, at which time it will be covered by the Safety of Human Cells, Tissues and Organs for Transplantation Regulations (CTO Regulations).
Review Strategy
The Medical Advisory Secretariat systematically reviewed the literature to assess the effectiveness and safety of LSCT for the treatment of patients with nonpterygium LSCD and pterygium. A comprehensive search method was used to retrieve English-language journal articles from selected databases.
The GRADE approach was used to systematically and explicitly evaluate the quality of evidence and strength of recommendations.
Summary of Findings
Nonpterygium Limbal Stem Cell Deficiency
The search identified 873 citations published between January 1, 2000, and March 31, 2008. Nine studies met the inclusion criteria, and 1 additional citation was identified through a bibliography review. The review included 10 case series (3 prospective and 7 retrospective).
Patients who received autologous transplants (i.e., CLAU) achieved significantly better long-term corneal surface results compared with patients who received allogeneic transplants (lr-CLAL, P< .001; KLAL, P< .001). There was no significant difference in corneal surface outcomes between the allogeneic transplant options, lr-CLAL and KLAL (P = .328). However, human leukocyte antigen matching and systemic immunosuppression may improve the outcome of lr-CLAL compared with KLAL. Regardless of graft type, patients with Stevens-Johnson syndrome had poorer long-term corneal surface outcomes.
Concurrent AMT was associated with poorer long-term corneal surface improvements. When the effect of the AMT was removed, the difference between autologous and allogeneic transplants was much smaller.
Patients who received CLAU transplants had a significantly higher rate of visual acuity improvements compared with those who received lr-CLAL transplants (P = .002). However, to achieve adequate improvements in vision, patients with deep corneal scarring will require a corneal transplant several months after the LSCT.
No donor eye complications were observed.
Epithelial rejection and microbial keratitis were the most common long-term complications associated with LSCT (complications occurred in 6%–15% of transplantations). These complications can result in graft failure, so patients should be monitored regularly following LSCT.
Pterygium
The search yielded 152 citations published between January 1, 2000 and May 16, 2008. Six randomized controlled trials (RCTs) that evaluated LSCT as an adjuvant therapy for the treatment of pterygium met the inclusion criteria and were included in the review.
Limbal stem cell transplantation was compared with CAU, AMT, and MMC. The results showed that CLAU significantly reduced the risk of pterygium recurrence compared with CAU (relative risk [RR], 0.09; 95% confidence interval [CI], 0.01–0.69; P = .02). CLAU reduced the risk of pterygium recurrence for primary pterygium compared with MMC, but this comparison did not reach statistical significance (RR, 0.48; 95% CI, 0.21–1.10; P = .08). Both AMT and CLAU had similar low rates of recurrence (2 recurrences in 43 patients and 4 in 46, respectively), and the RR was not significant (RR, 1.88; 95% CI, 0.37–9.5; P = .45). Since sample sizes in the included studies were small, failure to detect a significant difference between LSCT and AMT or MMC could be the result of type II error. Limbal stem cell transplantation as an adjuvant to excision is a relatively safe procedure as long-term complications were rare (< 2%).
GRADE Quality of Evidence
Nonpterygium Limbal Stem Cell Deficiency
The evidence for the analyses related to nonpterygium LSCD was based on 3 prospective and 7 retrospective case series. Thus, the GRADE quality of evidence is very low, and any estimate of effect is very uncertain.
Pterygium
The analyses examining LSCT as an adjuvant treatment option for pterygium were based on 6 RCTs. The quality of evidence for the overall body of evidence for each treatment option comparison was assessed using the GRADE approach. In each of the comparisons, the quality of evidence was downgraded due to serious or very serious limitations in study quality (individual study quality was assessed using the Jadad scale, and an assessment of allocation concealment and the degree of loss to follow-up), which resulted in low- to moderate-quality GRADE evidence ratings (low-quality evidence for the CLAU and AMT and CLAU and MMC comparisons, and moderate-quality evidence for the CLAU and CAU comparison).
Ontario Health System Impact Analysis
Nonpterygium Limbal Stem Cell Deficiency
Since 1999, Ontario’s out-of-country (OOC) program has approved and reimbursed 8 patients for LSCTs and 1 patient for LSCT consultations. Similarly, most Canadian provinces have covered OOC or out-of-province LSCTs. Several corneal experts in Ontario have the expertise to perform LSCTs.
As there are no standard guidelines for LSCT, patients who receive transplants OOC may not receive care aligned with the best evidence. To date, many of the patients from Ontario who received OOC LSCTs received concurrent AMTs, and the evidence from this analysis questions the use of this procedure. In addition, 1 patient received a cultured LSCT, a procedure that is considered investigational. Many patients with LSCD have bilateral disease and therefore require allogeneic transplants. These patients will require systemic and topical immunosuppression for several years after the transplant, perhaps indefinitely. Thus, systemic side effects associated with immunosuppression are a potential concern, and patients must be monitored regularly.
Amniotic membrane transplantation is a common addition to many ocular surface reconstruction procedures, including LSCT. Amniotic membranes are recovered from human placentas from planned, uneventful caesarean sections. Before use, serological screening of the donor’s blood should be conducted. However, there is still a theoretical risk of disease transmission associated with this procedure.
Financial Impact
For the patients who were reimbursed for OOC LSCTs, the average cost of LSCT per eye was $18,735.20 Cdn (range, $8,219.54–$33,933.32). However, the actual cost per patient is much higher as these costs do not include consultations and follow-up visits, multiple LSCTs, and any additional procedures (e.g., corneal transplants) received during the course of treatment OOC. When these additional costs were considered, the average cost per patient was $57,583 Cdn (range, $8,219.54–$130,628.20).
The estimated average total cost per patient for performing LSCT in Ontario is $2,291.48 Cdn (range, $951.48–$4,538.48) including hospital and physician fees. This cost is based on the assumption that LSCT is technically similar to a corneal transplant, an assumption which needs to be verified. The cost does not include corneal transplantations, which some proportion of patients receiving a LSCT will require within several months of the limbal transplant.
Pterygium
Pterygium recurrence rates after surgical excision are high, ranging from 24% to 89%. However, according to clinical experts, the rate of recurrence is low in Ontario. While there is evidence that the prevalence of pterygium is higher in the “pterygium belt,” there was no evidence to suggest different recurrence rates or disease severity by location or climate.
Conclusions
Nonpterygium Limbal Stem Cell Deficiency
Successful LSCTs result in corneal re-epithelialization and improved vision in patients with LSCD. However, patients who received concurrent AMT had poorer long-term corneal surface improvements. Conjunctival-limbal autologous transplantation is the treatment option of choice, but if it is not possible, living-related or cadaveric allogeneic transplants can be used. The benefits of LSCT outweigh the risks and burdens, as shown in Executive Summary Table 1. According to GRADE, these recommendations are strong with low- to very low-quality evidence.
Benefits, Risks, and Burdens – Nonpterygium Limbal Stem Cell Deficiency
Short- and long-term improvement in corneal surface (stable, normal corneal epithelium and decreased vascularization and opacity)
Improvement in vision (visual acuity and functional vision)
Long-term complications are experienced by 8% to 16% of patients
Risks associated with long-term immunosuppression for recipients of allogeneic grafts
Potential risk of induced LSCD in donor eyes
High cost of treatment (average cost per patient via OOC program is $57,583; estimated cost of procedure in Ontario is $2,291.48)
Costs are expressed in Canadian dollars.
GRADE of recommendation: Strong recommendation, low-quality or very low-quality evidence
benefits clearly outweigh risks and burdens
case series studies
strong, but may change if higher-quality evidence becomes available
Pterygium
Conjunctival-limbal autologous transplantations significantly reduced the risk of pterygium recurrence compared with CAU. No other comparison yielded statistically significant results, but CLAU reduced the risk of recurrence compared with MMC. However, the benefit of LSCT in Ontario is uncertain as the severity and recurrence of pterygium in Ontario is unknown. The complication rates suggest that CLAU is a safe treatment option to prevent the recurrence of pterygium. According to GRADE, given the balance of the benefits, risks, and burdens, the recommendations are very weak with moderate quality evidence, as shown in Executive Summary Table 2.
Benefits, Risks, and Burdens – Pterygium
Reduced recurrence; however, if recurrence is low in Ontario, this benefit might be minimal
Long-term complications rare
Increased cost
GRADE of recommendation: Very weak recommendations, moderate quality evidence.
uncertainty in the estimates of benefits, risks, and burden; benefits, risks, and burden may be closely balanced
RCTs
very weak, other alternatives may be equally reasonable
PMCID: PMC3377549  PMID: 23074512
23.  Community-Based Care for the Management of Type 2 Diabetes 
Executive Summary
In June 2008, the Medical Advisory Secretariat began work on the Diabetes Strategy Evidence Project, an evidence-based review of the literature surrounding strategies for successful management and treatment of diabetes. This project came about when the Health System Strategy Division at the Ministry of Health and Long-Term Care subsequently asked the secretariat to provide an evidentiary platform for the Ministry’s newly released Diabetes Strategy.
After an initial review of the strategy and consultation with experts, the secretariat identified five key areas in which evidence was needed. Evidence-based analyses have been prepared for each of these five areas: insulin pumps, behavioural interventions, bariatric surgery, home telemonitoring, and community based care. For each area, an economic analysis was completed where appropriate and is described in a separate report.
To review these titles within the Diabetes Strategy Evidence series, please visit the Medical Advisory Secretariat Web site, http://www.health.gov.on.ca/english/providers/program/mas/mas_about.html,
Diabetes Strategy Evidence Platform: Summary of Evidence-Based Analyses
Continuous Subcutaneous Insulin Infusion Pumps for Type 1 and Type 2 Adult Diabetics: An Evidence-Based Analysis
Behavioural Interventions for Type 2 Diabetes: An Evidence-Based Analysis
Bariatric Surgery for People with Diabetes and Morbid Obesity: An Evidence-Based Summary
Community-Based Care for the Management of Type 2 Diabetes: An Evidence-Based Analysis
Home Telemonitoring for Type 2 Diabetes: An Evidence-Based Analysis
Application of the Ontario Diabetes Economic Model (ODEM) to Determine the Cost-effectiveness and Budget Impact of Selected Type 2 Diabetes Interventions in Ontario
Objective
The objective of this report is to determine the efficacy of specialized multidisciplinary community care for the management of type 2 diabetes compared to usual care.
Clinical Need: Target Population and Condition
Diabetes (i.e. diabetes mellitus) is a highly prevalent chronic metabolic disorder that interferes with the body’s ability to produce or effectively use insulin. The majority (90%) of diabetes patients have type 2 diabetes. (1) Based on the United Kingdom Prospective Diabetes Study (UKPDS), intensive blood glucose and blood pressure control significantly reduce the risk of microvascular and macrovascular complications in type 2 diabetics. While many studies have documented that patients often do not meet the glycemic control targets specified by national and international guidelines, factors associated with glycemic control are less well studied, one of which is the provider(s) of care.
Multidisciplinary approaches to care may be particularly important for diabetes management. According guidelines from the Canadian Diabetes Association (CDA), the diabetes health care team should be multi-and interdisciplinary. Presently in Ontario, the core diabetes health care team consists of at least a family physician and/or diabetes specialist, and diabetes educators (registered nurse and registered dietician).
Increasing the role played by allied health care professionals in diabetes care and their collaboration with physicians may represent a more cost-effective option for diabetes management. Several systematic reviews and meta-analyses have examined multidisciplinary care programs, but these have either been limited to a specific component of multidisciplinary care (e.g. intensified education programs), or were conducted as part of a broader disease management program, of which not all were multidisciplinary in nature. Most reviews also do not clearly define the intervention(s) of interest, making the evaluation of such multidisciplinary community programs challenging.
Evidence-Based Analysis Methods
Research Questions
What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a registered nurse, registered dietician and physician (primary care and/or specialist) for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 1]
What is the evidence of efficacy of specialized multidisciplinary community care provided by at least a pharmacist and a primary care physician for the management of type 2 diabetes compared to usual care? [Henceforth referred to as Model 2]
Inclusion Criteria
English language full-reports
Published between January 1, 2000 and September 28, 2008
Randomized controlled trials (RCTs), systematic reviews and meta-analyses
Type 2 diabetic adult population (≥18 years of age)
Total sample size ≥30
Describe specialized multidisciplinary community care defined as ambulatory-based care provided by at least two health care disciplines (of which at least one must be a specialist in diabetes) with integrated communication between the care providers.
Compared to usual care (defined as health care provision by non-specialist(s) in diabetes, such as primary care providers; may include referral to other health care professionals/services as necessary)
≥6 months follow-up
Exclusion Criteria
Studies where discrete results on diabetes cannot be abstracted
Predominantly home-based interventions
Inpatient-based interventions
Outcomes of Interest
The primary outcomes for this review were glycosylated hemoglobin (rHbA1c) levels and systolic blood pressure (SBP).
Search Strategy
A literature search was performed on September 28, 2008 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cumulative Index to Nursing & Allied Health Literature (CINAHL), the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published between January 1, 2000 and September 28, 2008. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also examined for any additional relevant studies not identified through the search. Articles with unknown eligibility were reviewed with a second clinical epidemiologist, then a group of epidemiologists until consensus was established. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Given the high clinical heterogeneity of the articles that met the inclusion criteria, specific models of specialized multidisciplinary community care were examined based on models of care that are currently being supported in Ontario, models of care that were commonly reported in the literature, as well as suggestions from an Expert Advisory Panel Meeting held on January 21, 2009.
Summary of Findings
The initial search yielded 2,116 unique citations, from which 22 RCTs trials and nine systematic reviews published were identified as meeting the eligibility criteria. Of these, five studies focused on care provided by at least a nurse, dietician, and physician (primary care and/or specialist) model of care (Model 1; see Table ES 1), while three studies focused on care provided by at least a pharmacist and primary care physician (Model 2; see Table ES 2).
Based on moderate quality evidence, specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in HbA1c of 1.0% compared with usual care. The effects of this model on SBP, however, are uncertain compared with usual care, based on very-low quality evidence. Specialized multidisciplinary community care Model 2 has demonstrated a statistically and clinically significant reduction in both HbA1c of 1.05% (based on high quality evidence) and SBP of 7.13 mm Hg (based on moderate quality evidence) compared to usual care. For both models, the evidence does not suggest a preferred setting of care delivery (i.e., primary care vs. hospital outpatient clinic vs. community clinic).
Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 1
Mean change from baseline to follow-up between intervention and control groups
Summary of Results of Meta-Analyses of the Effects of Multidisciplinary Care Model 2
Mean change from baseline to follow-up between intervention and control groups
PMCID: PMC3377524  PMID: 23074528
24.  The Impact of eHealth on the Quality and Safety of Health Care: A Systematic Overview 
PLoS Medicine  2011;8(1):e1000387.
Aziz Sheikh and colleagues report the findings of their systematic overview that assessed the impact of eHealth solutions on the quality and safety of health care.
Background
There is considerable international interest in exploiting the potential of digital solutions to enhance the quality and safety of health care. Implementations of transformative eHealth technologies are underway globally, often at very considerable cost. In order to assess the impact of eHealth solutions on the quality and safety of health care, and to inform policy decisions on eHealth deployments, we undertook a systematic review of systematic reviews assessing the effectiveness and consequences of various eHealth technologies on the quality and safety of care.
Methods and Findings
We developed novel search strategies, conceptual maps of health care quality, safety, and eHealth interventions, and then systematically identified, scrutinised, and synthesised the systematic review literature. Major biomedical databases were searched to identify systematic reviews published between 1997 and 2010. Related theoretical, methodological, and technical material was also reviewed. We identified 53 systematic reviews that focused on assessing the impact of eHealth interventions on the quality and/or safety of health care and 55 supplementary systematic reviews providing relevant supportive information. This systematic review literature was found to be generally of substandard quality with regards to methodology, reporting, and utility. We thematically categorised eHealth technologies into three main areas: (1) storing, managing, and transmission of data; (2) clinical decision support; and (3) facilitating care from a distance. We found that despite support from policymakers, there was relatively little empirical evidence to substantiate many of the claims made in relation to these technologies. Whether the success of those relatively few solutions identified to improve quality and safety would continue if these were deployed beyond the contexts in which they were originally developed, has yet to be established. Importantly, best practice guidelines in effective development and deployment strategies are lacking.
Conclusions
There is a large gap between the postulated and empirically demonstrated benefits of eHealth technologies. In addition, there is a lack of robust research on the risks of implementing these technologies and their cost-effectiveness has yet to be demonstrated, despite being frequently promoted by policymakers and “techno-enthusiasts” as if this was a given. In the light of the paucity of evidence in relation to improvements in patient outcomes, as well as the lack of evidence on their cost-effectiveness, it is vital that future eHealth technologies are evaluated against a comprehensive set of measures, ideally throughout all stages of the technology's life cycle. Such evaluation should be characterised by careful attention to socio-technical factors to maximise the likelihood of successful implementation and adoption.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
There is considerable international interest in exploiting the potential of digital health care solutions, often referred to as eHealth—the use of information and communication technologies—to enhance the quality and safety of health care. Often accompanied by large costs, any large-scale expenditure on eHealth—such as electronic health records, picture archiving and communication systems, ePrescribing, associated computerized provider order entry systems, and computerized decision support systems—has tended to be justified on the grounds that these are efficient and cost-effective means for improving health care. In 2005, the World Health Assembly passed an eHealth resolution (WHA 58.28) that acknowledged, “eHealth is the cost-effective and secure use of information and communications technologies in support of health and health-related fields, including health-care services, health surveillance, health literature, and health education, knowledge and research,” and urged member states to develop and implement eHealth technologies. Since then, implementing eHealth technologies has become a main priority for many countries. For example, England has invested at least £12.8 billion in a National Programme for Information Technology for the National Health Service, and the Obama administration in the United States has committed to a US$38 billion eHealth investment in health care.
Why Was This Study Done?
Despite the wide endorsement of and support for eHealth, the scientific basis of its benefits—which are repeatedly made and often uncritically accepted—remains to be firmly established. A robust evidence-based perspective on the advantages on eHealth could help to suggest priority areas that have the greatest potential for benefit to patients and also to inform international eHealth deliberations on costs. Therefore, in order to better inform the international community, the authors systematically reviewed the published systematic review literature on eHealth technologies and evaluated the impact of these technologies on the quality and safety of health care delivery.
What Did the Researchers Do and Find?
The researchers divided eHealth technologies into three main categories: (1) storing, managing, and transmission of data; (2) clinical decision support; and (3) facilitating care from a distance. Then, implementing methods based on those developed by the Cochrane Collaboration and the NHS Service Delivery and Organisation Programme, the researchers used detailed search strategies and maps of health care quality, safety, and eHealth interventions to identify relevant systematic reviews (and related theoretical, methodological, and technical material) published between 1997 and 2010. Using these techniques, the researchers retrieved a total of 46,349 references from which they identified 108 reviews. The 53 reviews that the researchers finally selected (and critically reviewed) provided the main evidence base for assessing the impact of eHealth technologies in the three categories selected.
In their systematic review of systematic reviews, the researchers included electronic health records and picture archiving communications systems in their evaluation of category 1, computerized provider (or physician) order entry and e-prescribing in category 2, and all clinical information systems that, when used in the context of eHealth technologies, integrate clinical and demographic patient information to support clinician decision making in category 3.
The researchers found that many of the clinical claims made about the most commonly used eHealth technologies were not substantiated by empirical evidence. The evidence base in support of eHealth technologies was weak and inconsistent and importantly, there was insubstantial evidence to support the cost-effectiveness of these technologies. For example, the researchers only found limited evidence that some of the many presumed benefits could be realized; importantly, they also found some evidence that introducing these new technologies may on occasions also generate new risks such as prescribers becoming over-reliant on clinical decision support for e-prescribing, or overestimate its functionality, resulting in decreased practitioner performance.
What Do These Findings Mean?
The researchers found that despite the wide support for eHealth technologies and the frequently made claims by policy makers when constructing business cases to raise funds for large-scale eHealth projects, there is as yet relatively little empirical evidence to substantiate many of the claims made about eHealth technologies. In addition, even for the eHealth technology tools that have proven to be successful, there is little evidence to show that such tools would continue to be successful beyond the contexts in which they were originally developed. Therefore, in light of the lack of evidence in relation to improvements in patient outcomes, as well as the lack of evidence on their cost-effectiveness, the authors say that future eHealth technologies should be evaluated against a comprehensive set of measures, ideally throughout all stages of the technology's life cycle, and include socio-technical factors to maximize the likelihood of successful implementation and adoption in a given context. Furthermore, it is equally important that eHealth projects that have already been commissioned are subject to rigorous, multidisciplinary, and independent evaluation.
Additional Information
Please access these websites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000387.
The authors' broader study is: Car J, Black A, Anandan C, Cresswell K, Pagliari C, McKinstry B, et al. (2008) The Impact of eHealth on the Quality and Safety of Healthcare. Available at: http://www.haps.bham.ac.uk/publichealth/cfhep/001.shtml
More information is available on the World Health Assembly eHealth resolution
The World Health Organization provides information at the Global Observatory on eHealth, as well as a global insight into eHealth developments
The European Commission provides Information on eHealth in Europe and some examples of good eHealth practice
More information is provided on NHS Connecting for Health
doi:10.1371/journal.pmed.1000387
PMCID: PMC3022523  PMID: 21267058
25.  Comparison of pharmacological and non-pharmacological interventions to prevent delirium in critically ill patients: a protocol for a systematic review incorporating network meta-analyses 
Systematic Reviews  2016;5(1):153.
Background
Delirium is characterized by acute changes in mental status including inattention, disorganized thinking, and altered level of consciousness, and is highly prevalent in critically ill adults. Delirium has adverse consequences for both patients and the healthcare system; however, at this time, no effective treatment exists. The identification of effective prevention strategies is therefore a clinical and research imperative. An important limitation of previous reviews of delirium prevention is that interventions were considered in isolation and only direct evidence was used. Our systematic review will synthesize all existing data using network meta-analysis, a powerful statistical approach that enables synthesis of both direct and indirect evidence.
Methods
We will search Ovid MEDLINE, CINAHL, Embase, PsycINFO, and Web of Science from 1980 to March 2016. We will search the PROSPERO registry for protocols and the Cochrane Library for published systematic reviews. We will examine reference lists of pertinent reviews and search grey literature and the International Clinical Trials Registry Platform for unpublished studies and ongoing trials. We will include randomized and quasi-randomized trials of critically ill adults evaluating any pharmacological, non-pharmacological, or multi-component intervention for delirium prevention, administered in or prior to (i.e., peri-operatively) transfer to the ICU. Two authors will independently screen search results and extract data from eligible studies. Risk of bias assessments will be completed on all included studies. To inform our network meta-analysis, we will first conduct conventional pair-wise meta-analyses for primary and secondary outcomes using random-effects models. We will generate our network meta-analysis using a Bayesian framework, assuming a common heterogeneity parameter across all comparisons, and accounting for correlations in multi-arm studies. We will perform analyses using WinBUGS software.
Discussion
This systematic review will address the existing knowledge gap regarding best practices for delirium prevention in critically ill adults by synthesizing evidence from trials of pharmacological, non-pharmacological, and multi-component interventions administered in or prior to transfer to the ICU. Use of network meta-analysis will clarify which delirium prevention strategies are most effective in improving clinical outcomes while causing least harm. The network meta-analysis is a novel approach and will provide knowledge users and decision makers with comparisons of multiple interventions of delirium prevention strategies.
Systematic review registration
PROSPERO CRD42016036313
Electronic supplementary material
The online version of this article (doi:10.1186/s13643-016-0327-0) contains supplementary material, which is available to authorized users.
doi:10.1186/s13643-016-0327-0
PMCID: PMC5016934  PMID: 27609018
Delirium; Prevention; Intensive care unit; Network meta-analysis

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