Are Treatments More Effective than Placebos? A Systematic Review and Meta-Analysis

BackgroundPlacebos are widely used in clinical practice in spite of ethical restrictions. Whether such use is justified depends in part on the relative benefit of placebos compared to ‘active’ treatments. A direct test for differences between placebo and ‘active’ treatment effects has not been conducted.ObjectivesWe aimed to test for differences between treatment and placebo effects within similar trial populations.ResultsIn trials with continuous outcomes (n = 115) we found no difference between treatment and placebo effects (MD = −0.29, 95% CI −0.62 to 0.05, P = 0.10). In trials with binary outcomes (n = 37) treatments were significantly more effective than placebos (RRR = 0.72, 95%CI = 0.61 to 0.86, P = 0.0003). Treatment and placebo effects were not different in 22 out of 28 predefined subgroup analyses. Of the six subgroups with differences treatments were more effective than placebos in five. However when all criteria for reducing bias were ruled out (continuous outcomes) placebos were more effective than treatments (MD = 1.59, 95% CI = 0.40 to 2.77, P = 0.009).

Conclusions and Implications

Placebos and treatments often have similar effect sizes. Placebos with comparatively powerful effects can benefit patients either alone or as part of a therapeutic regime, and trials involving such placebos must be adequately blinded.     

What Are the Health Benefits of Active Travel? A Systematic Review of Trials and Cohort Studies

Background

Increasing active travel (primarily walking and cycling) has been widely advocated for reducing obesity levels and achieving other population health benefits. However, the strength of evidence underpinning this strategy is unclear. This study aimed to assess the evidence that active travel has significant health benefits.

Methods

The study design was a systematic review of (i) non-randomised and randomised controlled trials, and (ii) prospective observational studies examining either (a) the effects of interventions to promote active travel or (b) the association between active travel and health outcomes. Reports of studies were identified by searching 11 electronic databases, websites, reference lists and papers identified by experts in the field. Prospective observational and intervention studies measuring any health outcome of active travel in the general population were included. Studies of patient groups were excluded.

Results

Twenty-four studies from 12 countries were included, of which six were studies conducted with children. Five studies evaluated active travel interventions. Nineteen were prospective cohort studies which did not evaluate the impact of a specific intervention. No studies were identified with obesity as an outcome in adults; one of five prospective cohort studies in children found an association between obesity and active travel. Small positive effects on other health outcomes were found in five intervention studies, but these were all at risk of selection bias. Modest benefits for other health outcomes were identified in five prospective studies. There is suggestive evidence that active travel may have a positive effect on diabetes prevention, which may be an important area for future research.

Conclusions

Active travel may have positive effects on health outcomes, but there is little robust evidence to date of the effectiveness of active transport interventions for reducing obesity. Future evaluations of such interventions should include an assessment of their impacts on obesity and other health outcomes.     

How Are Academic Age,Productivity and Collaboration Related to Citing Behavior of Researchers?

References are an essential component of research articles and therefore of scientific communication. In this study we investigate referencing (citing) behavior in five diverse fields (astronomy, mathematics, robotics, ecology and economics) based on 213,756 core journal articles. At the macro level we find: (a) a steady increase in the number of references per article over the period studied (50 years), which in some fields is due to a higher rate of usage, while in others reflects longer articles and (b) an increase in all fields in the fraction of older, foundational references since the 1980s, with no obvious change in citing patterns associated with the introduction of the Internet. At the meso level we explore current (2006–2010) referencing behavior of different categories of authors (21,562 total) within each field, based on their academic age, productivity and collaborative practices. Contrary to some previous findings and expectations we find that senior researchers use references at the same rate as their junior colleagues, with similar rates of re-citation (use of same references in multiple papers). High Modified Price Index (MPI, which measures the speed of the research front more accurately than the traditional Price Index) of senior authors indicates that their research has the similar cutting-edge aspect as that of their younger colleagues. In all fields both the productive researchers and especially those who collaborate more use a significantly lower fraction of foundational references and have much higher MPI and lower re-citation rates, i.e., they are the ones pushing the research front regardless of researcher age. This paper introduces improved bibliometric methods to measure the speed of the research front, disambiguate lead authors in co-authored papers and decouple measures of productivity and collaboration.     

How Are Health Research Priorities Set in Low and Middle Income Countries? A Systematic Review of Published Reports

Background

Priority setting is increasingly recognised as essential for directing finite resources to support research that maximizes public health benefits and drives health equity. Priority setting processes have been undertaken in a number of low- and middle-income country (LMIC) settings, using a variety of methods. We undertook a critical review of reports of these processes.

Methods and Findings

We searched electronic databases and online for peer reviewed and non-peer reviewed literature. We found 91 initiatives that met inclusion criteria. The majority took place at the global level (46%). For regional or national initiatives, most focused on Sub Saharan Africa (49%), followed by East Asia and Pacific (20%) and Latin America and the Caribbean (18%). A quarter of initiatives aimed to cover all areas of health research, with a further 20% covering communicable diseases. The most frequently used process was a conference or workshop to determine priorities (24%), followed by the Child Health and Nutrition Initiative (CHNRI) method (18%). The majority were initiated by an international organization or collaboration (46%). Researchers and government were the most frequently represented stakeholders. There was limited evidence of any implementation or follow-up strategies. Challenges in priority setting included engagement with stakeholders, data availability, and capacity constraints.

Conclusions

Health research priority setting (HRPS) has been undertaken in a variety of LMIC settings. While not consistently used, the application of established methods provides a means of identifying health research priorities in a repeatable and transparent manner. In the absence of published information on implementation or evaluation, it is not possible to assess what the impact and effectiveness of health research priority setting may have been.     

Are Weeds Hitchhiking a Ride on Your Car? A Systematic Review of Seed Dispersal on Cars

When traveling in cars, we can unintentionally carry and disperse weed seed; but which species, and where are they a problem? To answer these questions, we systematically searched the scientific literature to identify all original research studies that assess seed transported by cars and listed the species with seed on/in cars. From the 13 studies that fit these criteria, we found 626 species from 75 families that have seed that can be dispersed by cars. Of these, 599 are listed as weeds in some part of the world, with 439 listed as invasive or naturalized alien species in one or more European countries, 248 are invasive/noxious weeds in North America, 370 are naturalized alien species in Australia, 167 are alien species in India, 77 are invasive species in China and 23 are declared weeds/invaders in South Africa. One hundred and one are classified as internationally important environmental weeds. Although most (487) were only recorded once, some species such as Chenopodium album, Poa pratensis and Trifolium repens were common among studies. Perennial graminoids seem to be favoured over annual graminoids while annual forbs are favoured over perennial forbs. Species characteristics including seed size and morphology and where the plants grew affected the probability that their seed was transported by cars. Seeds can be found in many different places on cars including under the chassis, front and rear bumpers, wheel wells and rims, front and back mudguards, wheel arches, tyres and on interior floor mats. With increasing numbers of cars and expanding road networks in many regions, these results highlight the importance of cars as a dispersal mechanism, and how it may favour invasions by some species over others. Strategies to reduce the risk of seed dispersal by cars include reducing seed on cars by mowing road verges and cleaning cars.     

Can Economic Analysis Contribute to Disease Elimination and Eradication? A Systematic Review

Background

Infectious diseases elimination and eradication have become important areas of focus for global health and countries. Due to the substantial up-front investments required to eliminate and eradicate, and the overall shortage of resources for health, economic analysis can inform decision making on whether elimination/eradication makes economic sense and on the costs and benefits of alternative strategies. In order to draw lessons for current and future initiatives, we review the economic literature that has addressed questions related to the elimination and eradication of infectious diseases focusing on: why, how and for whom?

Methods

A systematic review was performed by searching economic literature (cost-benefit, cost-effectiveness and economic impact analyses) on elimination/eradication of infectious diseases published from 1980 to 2013 from three large bibliographic databases: one general (SCOPUS), one bio-medical (MEDLINE/PUBMED) and one economic (IDEAS/REPEC).

Results

A total of 690 non-duplicate papers were identified from which only 43 met the inclusion criteria. In addition, only one paper focusing on equity issues, the “for whom?” question, was found. The literature relating to “why?” is the largest, much of it focusing on how much it would cost. A more limited literature estimates the benefits in terms of impact on economic growth with mixed results. The question of how to eradicate or eliminate was informed by an economic literature highlighting that there will be opportunities for individuals and countries to free-ride and that forms of incentives and/or disincentives will be needed. This requires government involvement at country level and global coordination. While there is little doubt that eliminating infectious diseases will eventually improve equity, it will only happen if active steps to promote equity are followed on the path to elimination and eradication.

Conclusion

The largest part of the literature has focused on costs and economic benefits of elimination/eradication. To a lesser extent, challenges associated with achieving elimination/eradication and ensuring equity have also been explored. Although elimination and eradication are, for some diseases, good investments compared with control, countries’ incentives to eliminate do not always align with the global good and the most efficient elimination strategies may not prioritize the poorest populations. For any infectious disease, policy-makers will need to consider realigning contrasting incentives between the individual countries and the global community and to assure that the process towards elimination/eradication considers equity.     

How ‘Idiopathic’ Is Adolescent Idiopathic Scoliosis? A Systematic Review on Associated Abnormalities

Background

Despite more than a century of dedicated research, the etiology and pathogenesis of adolescent idiopathic scoliosis (AIS) remain unclear. By definition, ‘idiopathic’ implies an unknown cause. Nevertheless, many abnormalities concomitant to AIS have been described, often with the suggestion that these abnormalities are related to etio-pathogenesis. Insight in the concomitant abnormalities may assist in improving the understanding of the etiological pathways of AIS. We aimed to systematically review and synthesize available studies on abnormalities concomitant to AIS.

Methods

Original studies comparing untreated AIS patients with healthy adolescents on abnormalities other than the deformity of the spine were retrieved from PubMed and Embase. We followed PRISMA guidelines and to quantify the relationship between each abnormality and AIS we used a best-evidence-syntheses for relating risk-of-bias to consistency of effect sizes.

Results

We identified 88 relevant citations, forty-seven carried high risk-of-bias and twenty studies did not report quantitative data in a sufficient manner. The remaining twenty-one publications failed to report data from before initiation of the deformity and blind assessments. These cross-sectional studies provided data on fourteen abnormalities concomitant to AIS. With our best-evidence-syntheses we were unable to find both strong evidence and a consistent pattern of occurrence for AIS and any of these abnormalities. From moderate risk-of-bias studies a relatively consistent pattern of occurrence for AIS and impaired gait control (4 studies; 155 subjects; Cohen’s d = 1.00) and decreased bone mineral density (2 studies; 954 subjects; Cohen’s d = −0.83) was found. For nine abnormalities a consistent pattern of occurrence with AIS was found, but the evidence for these was weak.

Conclusions

Based on the available literature, strong evidence is lacking for a consistent pattern of occurrence of AIS and any abnormality. The relevance for understanding the multifactorial etiology of AIS is very limited.     

Cardiovascular and Renal Outcomes of Renin–Angiotensin System Blockade in Adult Patients with Diabetes Mellitus: A Systematic Review with Network Meta-Analyses

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     

Are Ureaplasma spp. a Cause of Nongonococcal Urethritis? A Systematic Review and Meta-Analysis

Background

Nongonococcal urethritis (NGU) is the most common male reproductive tract syndrome. Ureaplasmas spp. including U. urealyticum and U. parvum, have been increasingly reported to be implicated in NGU. However, there are still many contradictions about their pathogenic role in NGU.

Aims

The goals of this study were to evaluate the association of Ureaplasmas spp. with NGU, and to compare the prevalence of Ureaplasmas spp. infection in China relative to the world average.

Methods

A systematic review and meta-analysis was conducted following standard guidelines for meta-analysis. The quality of included studies was assessed by Newcastle-Ottawa scale.

Results

A total of seven studies involving 1,507 NGU patients and 1,223 controls were eligible for meta-analysis. There was no significant difference in the Ureaplasma spp. positive rate between the NGU and control groups. However, the U. urealyticum positive rate was significantly higher in NGU patients compared to controls; the U. parvum positive rate was significantly higher in controls compared to NGU patients. Furthermore, within the NGU patient group, the positive rate of U. urealyticum was significantly higher than that of U. parvum, whereas within the control group, the opposite trend was observed. Compared to the world average, a significantly higher positive rate of Ureaplasma spp. was observed in both the NGU and control groups in China.

Conclusions

Our analysis supports that U. urealyticum, but not U. parvum, is an etiological agent in NGU. More detailed studies of these two species in China and the world could contribute to a better understanding of the epidemiology and pathogenesis, and facilitate the development of better strategies for treatment and prevention of NGU.     

What Is New for an Old Molecule? Systematic Review and Recommendations on the Use of Resveratrol

Background

Resveratrol is a natural compound suggested to have beneficial health effects. However, people are consuming resveratrol for this reason without having the adequate scientific evidence for its effects in humans. Therefore, scientific valid recommendations concerning the human intake of resveratrol based on available published scientific data are necessary. Such recommendations were formulated after the Resveratrol 2010 conference, held in September 2010 in Helsingør, Denmark.

Methodology

Literature search in databases as PubMed and ISI Web of Science in combination with manual search was used to answer the following five questions: ¹Can resveratrol be recommended in the prevention or treatment of human diseases?; ²Are there observed “side effects” caused by the intake of resveratrol in humans?; ³What is the relevant dose of resveratrol?; ⁴What valid data are available regarding an effect in various species of experimental animals?; ⁵Which relevant (overall) mechanisms of action of resveratrol have been documented?

Conclusions/Significance

The overall conclusion is that the published evidence is not sufficiently strong to justify a recommendation for the administration of resveratrol to humans, beyond the dose which can be obtained from dietary sources. On the other hand, animal data are promising in prevention of various cancer types, coronary heart diseases and diabetes which strongly indicate the need for human clinical trials. Finally, we suggest directions for future research in resveratrol regarding its mechanism of action and its safety and toxicology in human subjects.     

Are Child and Adolescent Responses to Placebo Higher in Major Depression than in Anxiety Disorders? A Systematic Review of Placebo-Controlled Trials

Background

In a previous report, we hypothesized that responses to placebo were high in child and adolescent depression because of specific psychopathological factors associated with youth major depression. The purpose of this study was to compare the placebo response rates in pharmacological trials for major depressive disorder (MDD), obsessive compulsive disorder (OCD) and other anxiety disorders (AD-non-OCD).

Methodology and Principal Findings

We reviewed the literature relevant to the use of psychotropic medication in children and adolescents with internalized disorders, restricting our review to double-blind studies including a placebo arm. Placebo response rates were pooled and compared according to diagnosis (MDD vs. OCD vs. AD-non-OCD), age (adolescent vs. child), and date of publication. From 1972 to 2007, we found 23 trials that evaluated the efficacy of psychotropic medication (mainly non-tricyclic antidepressants) involving youth with MDD, 7 pertaining to youth with OCD, and 10 pertaining to youth with other anxiety disorders (N = 2533 patients in placebo arms). As hypothesized, the placebo response rate was significantly higher in studies on MDD, than in those examining OCD and AD-non-OCD (49.6% [range: 17–90%] vs. 31% [range: 4–41%] vs. 39.6% [range: 9–53], respectively, ANOVA F = 7.1, p = 0.002). Children showed a higher stable placebo response within all three diagnoses than adolescents, though this difference was not significant. Finally, no significant effects were found with respect to the year of publication.

Conclusion

MDD in children and adolescents appears to be more responsive to placebo than other internalized conditions, which highlights differential psychopathology.     

Do Interventions Designed to Support Shared Decision-Making Reduce Health Inequalities? A Systematic Review and Meta-Analysis

Background

Increasing patient engagement in healthcare has become a health policy priority. However, there has been concern that promoting supported shared decision-making could increase health inequalities.

Objective

To evaluate the impact of SDM interventions on disadvantaged groups and health inequalities.

Design

Systematic review and meta-analysis of randomised controlled trials and observational studies.

Data Sources

CINAHL, the Cochrane Register of Controlled Trials, the Cochrane Database of Systematic Reviews, EMBASE, HMIC, MEDLINE, the NHS Economic Evaluation Database, Open SIGLE, PsycINFO and Web of Knowledge were searched from inception until June 2012.

Study Eligibility Criteria

We included all studies, without language restriction, that met the following two criteria: (1) assess the effect of shared decision-making interventions on disadvantaged groups and/or health inequalities, (2) include at least 50% of people from disadvantaged groups, except if a separate analysis was conducted for this group.

Results

We included 19 studies and pooled 10 in a meta-analysis. The meta-analyses showed a moderate positive effect of shared decision-making interventions on disadvantaged patients. The narrative synthesis suggested that, overall, SDM interventions increased knowledge, informed choice, participation in decision-making, decision self-efficacy, preference for collaborative decision making and reduced decisional conflict among disadvantaged patients. Further, 7 out of 19 studies compared the intervention''s effect between high and low literacy groups. Overall, SDM interventions seemed to benefit disadvantaged groups (e.g. lower literacy) more than those with higher literacy, education and socioeconomic status. Interventions that were tailored to disadvantaged groups'' needs appeared most effective.

Conclusion

Results indicate that shared decision-making interventions significantly improve outcomes for disadvantaged patients. According to the narrative synthesis, SDM interventions may be more beneficial to disadvantaged groups than higher literacy/socioeconomic status patients. However, given the small sample sizes and variety in the intervention types, study design and quality, those findings should be interpreted with caution.     

How Does Medical Device Regulation Perform in the United States and the European Union? A Systematic Review

Background

Policymakers and regulators in the United States (US) and the European Union (EU) are weighing reforms to their medical device approval and post-market surveillance systems. Data may be available that identify strengths and weakness of the approaches to medical device regulation in these settings.

Methods and Findings

We performed a systematic review to find empirical studies evaluating medical device regulation in the US or EU. We searched Medline using two nested categories that included medical devices and glossary terms attributable to the US Food and Drug Administration and the EU, following PRISMA guidelines for systematic reviews. We supplemented this search with a review of the US Government Accountability Office online database for reports on US Food and Drug Administration device regulation, consultations with local experts in the field, manual reference mining of selected articles, and Google searches using the same key terms used in the Medline search. We found studies of premarket evaluation and timing (n = 9), studies of device recalls (n = 8), and surveys of device manufacturers (n = 3). These studies provide evidence of quality problems in pre-market submissions in the US, provide conflicting views of device safety based largely on recall data, and relay perceptions of some industry leaders from self-surveys.

Conclusions

Few studies have quantitatively assessed medical device regulation in either the US or EU. Existing studies of US and EU device approval and post-market evaluation performance suggest that policy reforms are necessary for both systems, including improving classification of devices in the US and promoting transparency and post-market oversight in the EU. Assessment of regulatory performance in both settings is limited by lack of data on post-approval safety outcomes. Changes to these device approval and post-marketing systems must be accompanied by ongoing research to ensure that there is better assessment of what works in either setting. Please see later in the article for the Editors'' Summary.     

What Has Finite Element Analysis Taught Us about Diabetic Foot Disease and Its Management? A Systematic Review

Background

Over the past two decades finite element (FE) analysis has become a popular tool for researchers seeking to simulate the biomechanics of the healthy and diabetic foot. The primary aims of these simulations have been to improve our understanding of the foot’s complicated mechanical loading in health and disease and to inform interventions designed to prevent plantar ulceration, a major complication of diabetes. This article provides a systematic review and summary of the findings from FE analysis-based computational simulations of the diabetic foot.

Methods

A systematic literature search was carried out and 31 relevant articles were identified covering three primary themes: methodological aspects relevant to modelling the diabetic foot; investigations of the pathomechanics of the diabetic foot; and simulation-based design of interventions to reduce ulceration risk.

Results

Methodological studies illustrated appropriate use of FE analysis for simulation of foot mechanics, incorporating nonlinear tissue mechanics, contact and rigid body movements. FE studies of pathomechanics have provided estimates of internal soft tissue stresses, and suggest that such stresses may often be considerably larger than those measured at the plantar surface and are proportionally greater in the diabetic foot compared to controls. FE analysis allowed evaluation of insole performance and development of new insole designs, footwear and corrective surgery to effectively provide intervention strategies. The technique also presents the opportunity to simulate the effect of changes associated with the diabetic foot on non-mechanical factors such as blood supply to local tissues.

Discussion

While significant advancement in diabetic foot research has been made possible by the use of FE analysis, translational utility of this powerful tool for routine clinical care at the patient level requires adoption of cost-effective (both in terms of labour and computation) and reliable approaches with clear clinical validity for decision making.     

Are Reports of Psychological Stress Higher in Occupational Studies? A Systematic Review across Occupational and Population Based Studies

Objectives

The general health questionnaire (GHQ) is commonly used to assess symptoms of common mental disorder (CMD). Prevalence estimates for CMD caseness from UK population studies are thought to be in the range of 14–17%, and the UK occupational studies of which we are aware indicate a higher prevalence. This review will synthesise the existing research using the GHQ from both population and occupational studies and will compare the weighted prevalence estimates between them.

Methods

We conducted a systematic review and meta-analysis to examine the prevalence of CMD, as assessed by the GHQ, in all UK occupational and population studies conducted from 1990 onwards.

Results

The search revealed 65 occupational papers which met the search criteria and 15 relevant papers for UK population studies. The weighted prevalence estimate for CMD across all occupational studies which used the same version and cut-off for the GHQ was 29.6% (95% confidence intervals (CIs) 27.3–31.9%) and for comparable population studies was significantly lower at 19.1% (95% CIs 17.3–20.8%). This difference was reduced after restricting the studies by response rate and sampling method (23.9% (95% CIs 20.5%–27.4%) vs. 19.2% (95 CIs 17.1%–21.3%)).

Conclusions

Counter intuitively, the prevalence of CMD is higher in occupational studies, compared to population studies (which include individuals not in employment), although this difference narrowed after accounting for measures of study quality, including response rate and sampling method. This finding is inconsistent with the healthy worker effect, which would presume lower levels of psychological symptoms in individuals in employment. One explanation is that the GHQ is sensitive to contextual factors, and it seems possible that symptoms of CMD are over reported when participants know that they have been recruited to a study on the basis that they belong to a specific occupational group, as in nearly all “stress” surveys.     

When Are Statins Cost-Effective in Cardiovascular Prevention? A Systematic Review of Sponsorship Bias and Conclusions in Economic Evaluations of Statins

Background

We examined sponsorship of published cost-effectiveness analyses of statin use for cardiovascular (CV) prevention, and determined whether the funding source is associated with study conclusions.

Methods and Findings

We searched PubMed/MEDLINE (up to June 2011) to identify cost-effectiveness analyses of statin use for CV prevention reporting outcomes as incremental costs per quality-adjusted life years (QALY) and/or life years gained (LYG). We examined relationships between the funding source and the study conclusions by means of tests of differences between proportions. Seventy-five studies were included. Forty-eight studies (64.0%) were industry-sponsored. Fifty-two (69.3%) articles compared statins versus non-active alternatives. Secondary CV prevention represented 42.7% of articles, followed by primary CV prevention (38.7%) and both (18.7%). Overall, industry-sponsored studies were much less likely to report unfavourable or neutral conclusions (0% versus 37.1%; p<0.001). For primary CV prevention, the proportion with unfavourable or neutral conclusions was 0% for industry-sponsored studies versus 57.9% for non-sponsored studies (p<0.001). Conversely, no statistically significant differences were identified for studies evaluating secondary CV prevention (0% versus 12.5%; p=0.222). Incremental costs per QALY/LYG estimates reported in industry-sponsored studies were generally more likely to fall below a hypothetical willingness-to-pay threshold of US $50,000.

Conclusions

Our systematic analysis suggests that pharmaceutical industry sponsored economic evaluations of statins have generally favored the cost-effectiveness profile of their products particularly in primary CV prevention.     

Efficacy of Second Generation Direct-Acting Antiviral Agents for Treatment Na?ve Hepatitis C Genotype 1: A Systematic Review and Network Meta-Analysis

Background

The treatment of hepatitis C (HCV) infections has significantly changed in the past few years due to the introduction of direct-acting antiviral agents (DAAs). DAAs could improve the sustained virological response compared to pegylated interferon with ribavirin (PR). However, there has been no evidence from randomized controlled trials (RCTs) that directly compare the efficacy among the different regimens of DAAs.

Aim

Therefore, we performed a systematic review and network meta-analysis aiming to compare the treatment efficacy between different DAA regimens for treatment naïve HCV genotype 1.

Methods

Medline and Scopus were searched up to 25^th May 2015. RCTs investigating the efficacy of second generation DAA regimens for treatment naïve HCV genotype 1 were eligible for the review. Due to the lower efficacy and more side effects of first generation DAAs, this review included only second generation DAAs approved by the US or EU Food and Drug Administration, that comprised of simeprevir (SMV), sofosbuvir (SOF), daclatasvir (DCV), ledipasvir (LDV), and paritaprevir/ritonavir/ombitasvir plus dasabuvir (PrOD). Primary outcomes were sustained virological response at weeks 12 (SVR12) and 24 (SVR24) after the end of treatment and adverse drug events (i.e. serious adverse events, anemia, and fatigue). Efficacy of all treatment regimens were compared by applying a multivariate random effect meta-analysis. Incidence rates of SVR12 and SVR24, and adverse drug events of each treatment regimen were pooled using ‘pmeta’ command in STATA program.

Results

Overall, 869 studies were reviewed and 16 studies were eligible for this study. Compared with the PR regimen, SOF plus PR, SMV plus PR, and DVC plus PR regimens yielded significantly higher probability of having SVR24 with pooled risk ratios (RR) of 1.98 (95% CI 1.24, 3.14), 1.46 (95% CI: 1.22, 1.75), and 1.68 (95% CI: 1.14, 2.46), respectively. Pooled incidence rates of SVR12 and SVR24 in all treatment regimens without PR, i.e. SOF plus LDV with/without ribavirin, SOF plus SMV with/without ribavirin, SOF plus DCV with/without ribavirin, and PrOD with/without ribavirin, (pooled incidence of SVR12 ranging from 93% to 100%, and pooled incidence of SVR24 ranging from 89% to 96%) were much higher than the pooled incidence rates of SVR12 (51%) and SVR24 (48%) in PR alone. In comparing SOF plus LDV with ribavirin and SOF plus LDV without ribavirin, the chance of having SVR12 was not significantly different between these two regimens, with the pooled RR of 0.99 (95% CI: 0.97, 1.01). Regarding adverse drug events, risk of serious adverse drug events, anemia and fatigue were relatively higher in treatment regimens with PR than the treatment regimens without PR. The main limitation of our study is that a subgroup analysis according to dosages and duration of treatment could not be performed. Therefore, the dose and duration of recommended treatment have been suggested in range and not in definite value.

Conclusions

Both DAA plus PR and dual DAA regimens should be included in the first line drug for treatment naïve HCV genotype 1 because of the significant clinical benefits over PR alone. However, due to high drug costs, an economic evaluation should be conducted in order to assess the value of the investment when making coverage decisions.