Alessandro Liberati

Antibiotic prophylaxis to reduce respiratory tract infections and mortality in adults receiving intensive care

BACKGROUNDnPneumonia is an important cause of mortality in intensive care units (ICUs). The incidence of pneumonia in ICU patients ranges between 7% and 40%, and the crude mortality from ventilator-associated pneumonia may exceed 50%. Although not all deaths in patients with this form of pneumonia are directly attributable to pneumonia, it has been shown to contribute to mortality in ICUs independently of other factors that are also strongly associated with such deaths.nnnOBJECTIVESnTo assess the effects of prophylactic antibiotic regimens, such as selective decontamination of the digestive tract (SDD) for the prevention of respiratory tract infections (RTIs) and overall mortality in adults receiving intensive care.nnnSEARCH STRATEGYnWe searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2009, issue 1), which contains the Cochrane Acute Respiratory Infections (ARI) Groups Specialised Register; MEDLINE (January 1966 to March 2009); and EMBASE (January 1990 to March 2009).nnnSELECTION CRITERIAnRandomised controlled trials (RCTs) of antibiotic prophylaxis for RTIs and deaths among adult ICU patients.nnnDATA COLLECTION AND ANALYSISnAt least two review authors independently extracted data and assessed trial quality.nnnMAIN RESULTSnWe included 36 trials involving 6914 people. There was variation in the antibiotics used, patient characteristics and risk of RTIs and mortality in the control groups. In trials comparing a combination of topical and systemic antibiotics, there was a significant reduction in both RTIs (number of studies = 16, odds ratio (OR) 0.28, 95% confidence interval (CI) 0.20 to 0.38) and total mortality (number of studies = 17, OR 0.75, 95% CI 0.65 to 0.87) in the treated group. In trials comparing topical antimicrobials alone (or comparing topical plus systemic versus systemic alone) there was a significant reduction in RTIs (number of studies = 17, OR 0.44, 95% CI 0.31 to 0.63) but not in total mortality (number of studies = 19, OR 0.97, 95% CI 0.82 to 1.16) in the treated group.nnnAUTHORS CONCLUSIONSnA combination of topical and systemic prophylactic antibiotics reduces RTIs and overall mortality in adult patients receiving intensive care. Treatment based on the use of topical prophylaxis alone reduces respiratory infections but not mortality. The risk of resistance occurring as a negative consequence of antibiotic use was appropriately explored only in one trial which did not show any such effect.

Follow‐up strategies for women treated for early breast cancer

BACKGROUNDnFollow-up examinations are commonly performed after primary treatment for women with breast cancer. They are used to detect recurrences at an early (asymptomatic) stage. This is an update of a Cochrane review first published in 2000.nnnOBJECTIVESnTo assess the effectiveness of different policies of follow-up for distant metastases on mortality, morbidity and quality of life in women treated for stage I, II or III breast cancer.nnnSEARCH METHODSnFor this 2014 review update, we searched the Cochrane Breast Cancer Groups Specialised Register (4 July 2014), MEDLINE (4 July 2014), Embase (4 July 2014), CENTRAL (2014, Issue 3), thexa0World Health Organization (WHO) International Clinical Trials Registry Platform (4 July 2014) and ClinicalTrials.gov (4 July 2014). References from retrieved articles were also checked.nnnSELECTION CRITERIAnAll randomised controlled trials (RCTs) assessing the effectiveness of different policies of follow-up after primary treatment were reviewed for inclusion.nnnDATA COLLECTION AND ANALYSISnTwo review authors independently assessed trials for eligibility for inclusion in the review and risk of bias. Data were pooled in an individual patient data meta-analysis for the two RCTs testing the effectiveness of different follow-up schemes. Subgroup analyses were conducted by age, tumour size and lymph node status.nnnMAIN RESULTSnSince 2000, one new trial has been published; the updated review now includes five RCTs involving 4023 women with breast cancer (clinical stage I, II or III).Two trials involving 2563 women compared follow-up based on clinical visits and mammography with a more intensive scheme including radiological and laboratory tests. After pooling the data, no significant differences in overall survival (hazard ratio (HR) 0.98, 95% confidence interval (CI) 0.84 to 1.15, two studies, 2563 participants, high-quality evidence), or disease-free survival (HR 0.84, 95% CI 0.71 to 1.00, two studies, 2563 participants, low-quality evidence) emerged. No differences in overall survival and disease-free survival emerged in subgroup analyses according to patient age, tumour size and lymph node status before primary treatment. In 1999, 10-year follow-up data became available for one trial of these trials, and no significant differences in overall survival were found. No difference was noted in quality of life measures (one study, 639 participants, high-quality evidence).The new included trial, together with a previously included trial involving 1264 women compared follow-up performed by a hospital-based specialist versus follow-up performed by general practitioners. No significant differences were noted in overall survival (HR 1.07, 95% CI 0.64 to 1.78, one study, 968 participants, moderate-quality evidence), time to detection of recurrence (HR 1.06, 95% CI 0.76 to 1.47, two studies, 1264 participants, moderate-quality evidence), and quality of life (one study, 356 participants, high-quality evidence). Patient satisfaction was greater among patients treated by general practitioners. One RCT involving 196 women compared regularly scheduled follow-up visits versus less frequent visits restricted to the time of mammography. No significant differences emerged in interim use of telephone and frequency of general practitionerss consultations.nnnAUTHORS CONCLUSIONSnThis updated review of RCTs conducted almost 20 years ago suggests that follow-up programs based on regular physical examinations and yearly mammography alone are as effective as more intensive approaches based on regular performance of laboratory and instrumental tests in terms of timeliness of recurrence detection, overall survival and quality of life.In two RCTs, follow-up care performed by trained and not trained general practitioners working in an organised practice setting had comparable effectiveness to that delivered by hospital-based specialists in terms of overall survival, recurrence detection, and quality of life.

Compliance of clinical trial registries with the World Health Organization minimum data set: a survey

BackgroundSince September 2005 the International Committee of Medical Journal Editors has required that trials be registered in accordance with the World Health Organization (WHO) minimum dataset, in order to be considered for publication. The objective is to evaluate registries and individual trial records compliance with the 2006 version of the WHO minimum data set.MethodsA retrospective evaluation of 21 online clinical trial registries (international, national, specialty, pharmaceutical industry and local) from April 2005 to February 2007 and a cross-sectional evaluation of a stratified random sample of 610 trial records from the 21 registries.ResultsAmong 11 registries that provided guidelines for registration, the median compliance with the WHO criteria were 14 out of 20 items (range 6 to 20). In the period April 2005–February 2007, six registries increased their compliance by six data items, on average. None of the local registry websites published guidelines on the trial data items required for registration. Slightly more than half (330/610; 54.1%, 95% CI 50.1% – 58.1%) of trial records completed the contact details criteria while 29.7% (181/610, 95% CI 26.1% – 33.5%) completed the key clinical and methodological data fields.ConclusionWhile the launch of the WHO minimum data set seemed to positively influence registries with better standardisation of approaches, individual registry entries are largely incomplete. Initiatives to ensure quality assurance of registries and trial data should be encouraged. Peer reviewers and editors should scrutinise clinical trial registration records to ensure consistency with WHOs core content requirements when considering trial-related publications.

Clinical evidence continuous medical education: a randomised educational trial of an open access e-learning program for transferring evidence-based information – ICEKUBE (Italian Clinical Evidence Knowledge Utilization Behaviour Evaluation) – study protocol

BackgroundIn an effort to ensure that all physicians have access to valid and reliable evidence on drug effectiveness, the Italian Drug Agency sponsored a free-access e-learning system, based on Clinical Evidence, called ECCE. Doctors have access to an electronic version and related clinical vignettes. Correct answers to the interactive vignettes provide Continuing Medical Education credits. The aims of this trial are to establish whether the e-learning program (ECCE) increases physicians basic knowledge about common clinical scenarios, and whether ECCE is superior to the passive diffusion of information through the printed version of Clinical Evidence.DesignAll Italian doctors naïve to ECCE will be randomised to three groups. Group one will have access to ECCE for Clinical Evidence chapters and vignettes lot A and will provide control data for Clinical Evidence chapters and vignettes lot B; group two vice versa; group three will receive the concise printed version of Clinical Evidence. There are in fact two designs: a before and after pragmatic trial utilising a two by two incomplete block design (group one versus group two) and a classical design (group one and two versus group three). The primary outcome will be the retention of Clinical Evidence contents assessed from the scores for clinical vignettes selected from ECCE at least six months after the intervention. To avoid test-retest effects, we will randomly select vignettes out of lot A and lot B, avoiding repetitions. In order to preserve the comparability of lots, we will select vignettes with similar, optimal psychometric characteristics.Trial registrationISRCTN27453314

When drug companies select what they want to publish patients are denied relevant therapeutic information

The methodologist’s point of viewGraziella Filippini, Lorenzo Moja, Alessandro LiberatiCochrane ReviewType-1 interferons are recommended as the first-linetreatment of multiple sclerosis (MS) in North Americanand European guidelines [1–3]. The efficacy of interferonson delaying disability progression—the most importantgoal of treatment in this 30–40 year disease—has beenevaluated in one Cochrane Review including five ran-domized, placebo control trials of either interferon beta-1b (two trials), or interferon beta-1a (three trials)involving 1,130 patients with relapsing-remitting MS(RRMS) [4]. From the available data in three of thesetrials, the authors of the review calculated an absolute riskreduction (ARR) of 9% (95% CI: 3.14%) of RRMSpatients who progressed in 2 years. However, when allpatients randomised in the trials were re-analysed bysensitivity analysis (overall 20% of patients had beenexcluded after randomization or were lost to follow-upduring the intervention), statistical significance was lost,providing an ARR of -10% (95% CI -38.18%). At2 years’ follow-up data were not robust or dropoutscompromised interpretation: for instance, in one trialfollow-up data were available on less than 40% of ran-domised patients. The number of patients who hadrelapses during the first 2 years fell significantly in theper protocol analysis (ARR 14%; 95% CI 8.19%), but,again, results were inconclusive after sensitivity analyses.All extended trials’ observations beyond 2 years wereopen, hampering an evaluation of long-term effect of in-terferons in delaying progression of RRMS patients.All individual studies included in this review weresponsored by the pharmaceutical companies producinginterferon beta: the data presented by companies in medicaljournal publications were actually selective reporting ofpatients who adhered to the interferons. This approach isknown as a per protocol analysis (also known as efficacy orexplanatory analysis) which counts the outcomes of thepatients who adhered to the research protocol [5]. Notsurprisingly these patients tended to have a better prognosisas opposed to the patients that had not adhered. Excludingdropouts from the analysis influenced the nature of the finalresults (both in terms of direction and/or magnitude). The

Measuring the impact of evidence: the Cochrane systematic review of organised stroke care

In 2007, the first commentary hosted by this Cochrane’s Corner focussed on stroke units and discussed the principle that a valid combination of results from a series of unbiased primary studies can provide influential information that would not be otherwise available by individual studies [1]. We now present a case study of the role played by the stroke unit Cochrane review in the complicated process that led to changes in clinical practice and health policy. Our hypothesis is that the theoretical and pragmatic value of this systematic review goes beyond the mere increase in the number of patients considered in one study: robust results from a methodologically sound systematic review including trials performed in different setting and with different standards can increase the applicability of the conclusion.

Rimonabant for overweight and “metabolic syndrome”: the attempt to supersize disease and risk by pharmaceutical marketing

A Cochrane systematic review explored the potential role of rimonabant for overweight and obesity [1]. On the basis of surrogate outcomes reported in the included RCTs, rimonabant has been a candidate (by its producer) to act as a pleiotropic agent for the entire cardiovascular risk spectrum. Is this compelling evidence to consider rimonabant the new panacea for the ‘‘metabolic syndrome’’ or are we facing another attempt of disease mongering by a new market frontier? Rimonabant has been shown to reduce food intake, appetite and body weight in overweight or obese people. Four randomized controlled trials (RIO-Europe [2], RIONorth America [3], RIO-diabetes [4], RIO-lipids [5]) evaluated rimonabant 20 mg versus rimonabant 5 mg versus placebo. All interventions were given over 1 year and included the addition of a hypocaloric diet. All trials were designed, conducted and reported with the contribution of Sanofi-Aventis drug company. The Cochrane review (‘‘Rimonabant for overweight and obesity’’) [1] includes evidence from these four trials.

Scales to climb borderline personalities: when science goes nowhere

Although these psychosocial scales are increasingly used, scepticism and confusion remain regarding the ability of many scales to summarise composite indices and if they are meaningful in orienting a conclusive clinical decision. We explore some of the limitations regarding scales use and misuse in science. The purpose of the review by Binks et al. [1] is to evaluate the evidence for the efficacy of psychological intervention for people with BPD. This review is extremely important from a policy standpoint given the prevalence of the problem (2%), the association with deliberate selfharm and suicide, and the long-term cost to the healthcare system due to chronicity and intense health service demands by people with BPD. The Authors expected that outcomes would not have been consistently reported across the included trials and that different measures of disease and scales had been used (e.g., quality of life, mental state, behaviour, etc.). In order not to miss useful observations, the Authors included data from any rating scale as long as these instruments had been described in a peer-reviewed journal. This broad approach resulted in 15 outcome categories, each of which has several measures, totalling 82 outcomes. There are six primary outcomes, placed in five different categories. For example, the category mental state is articulated in: (1) general mental state; (2) not clinically important change in general mental state (a primary outcome); (3) not any change in general mental state; and ... etc. Death is the only outcome with no subcategories. The advantage of the choice made by the Authors is that the whole body of research on this topic is covered, but at what price? The disadvantage is that a general reader will not go through this review as he will find himself lost trying to understand the essence of the trial results. Even a psychologist using a methodological approach will be puzzled by the question: Which is an effective treatment for borderline personality disorders? This is not easy to answer given the multitude and fragmentation of the instruments and outcomes presented in the review.

Selecting references that match constructs: the difficult job of citing the parachute hyperbole.

The large scale availability of clotting factor concentrates and the organization of comprehensive care centres prompted a progressive increase in the life expectancy and quality of life of western world haemophilia patients [1, 2]. The best treatment regimen for haemophilia, across the world being considered, is regular prophylactic replacement with clotting factor concentrates. Strong observational evidence has been available since long time in support of this widely established pattern of practice; 26 unique observational studies of varying quality for a total of 1,612 patients on prophylaxis compared to 1,191 patients treated ondemand were reported through 2005 [3]. Notwithstanding this evidence and in front of several open questions about optimization of prophylactic regimen (i.e., onset, frequency, intensity, duration, patient selection), the directors of the Canadian Association of Haemophilia Centres prompted and sponsored a Cochrane Review on the topic. The systematic review found very little randomized controlled trial (RCT)-based evidence in this field; there were only four trials with a total of 37 patients [3]. All trials enrolled adult patients already affected by various degree of arthropathy, so that virtually no direct RCT-based information was available about primary prophylaxis in young children devoid of any joint damage [4]. The authors concluded that ‘‘There is insufficient evidence from randomised controlled trials to determine whether prophylactic clotting factor concentrates decrease bleeding and bleeding-related complications in hemophilia A or B, compared to placebo, ondemand treatment, or prophylaxis based on pharmacokinetic data from individuals. Well-designed RCTs are needed to assess the effectiveness of prophylactic clotting factor concentrates. Two clinical trials are ongoing.’’ The aforementioned Cochrane Review prompted a sustained debate about the need and ethicality of RCTs in the haemophilia field. A popular BMJ paper by Smith and Pell about the lack of evidence that parachutes are worth wearing if jumping from airplanes [5] was cited in support by those claiming against the need of RCTs [6]. The clever and humorous BMJ paper is widely cited, but it was miscited in the specific case of the haemophilia review as in many others. This commentary will try to put ‘‘the parachute hyperbole’’ in the right perspective, offering a brief discussion about how to go from particular instance (i.e., RCTs to experimentally test parachute) to the high order A. Iorio Stroke Unit and Division of Cardiovascular Medicine, Department of Internal Medicine, University of Perugia, Perugia, Italy

Renaissance of ares publica clinical research: global access to trial registers

The pivotal importance of registering clinical trials is increasingly accepted, and several governmental and non-governmental bodies, including the Italian Ministry of Health, have developed guidelines or set up registries in recent years and months1. Three initiatives at the international level seem to us to foster the global awareness of the ethical and scientific obligation to register clinical trials. First, the International Committee of Medical Journal Editors (ICMJE) initiative2. Several decades since the idea of registering clinical trials was first proposed, the ICMJE took a significant step to urge academics and researchers to use the registers: after July 1, 2005, trials that are not registered will not be considered for publication in the medical journals that adhere to the ICMJE initiative. Which studies are eligible then? All trials in which volunteers are prospectively assigned to a medical intervention or a control, and in which a causal-relationship between the intervention and an outcome is the focus2. Medical interventions include drugs as well as surgical procedures, behavioural treatments and quality improvement processes. Only trials looking at pharmacokinetics and early toxicity are clearly excluded. To maintain an accessible and informative process, the ICMJE is supporting freely accessible and not for profit registers, and the 20 item World Health Organisation (WHO) minimum data set that requires key clinical and methodological fields3. The WHO minimal data set is part of the second landmark initiative to build up the International Clinical Trial Registry Platform4. This WHO entity coordinates an international network of primary registers to harmonise registration across the world. The national and international registers ensure the collection of all required items, data entry validation and other aspects of quality assurance. Several registers expanded their list of items in response to this initiative. We particularly recommend registering trials in two international registers: the US National Library of Medicine’s ClinicalTrials.gov5 and the UK’s Current Controlled Trials International Standard Randomised Controlled Trials Number Register (ISRCTN)6. Both are widely known, and ensure a process to update data and reduce the possibility of duplicate registration. The third initiative, known as the Ottawa Statement, is a consensus document from an international group of researchers with a close connection to and support by The Cochrane Collaboration7. The aim of this group of researchers is to provide a set of guiding principles for the development of trial registers. The first document lists principles for development, while the second document makes the principles operational8. For example, the first principle states that every trial should have a unique ID assigned by a single international source. The proposed mechanism to make this operational is that WHO assigns a Universal Reference Trial Number for a global unique ID. The Italian translation of the Ottawa Statement, Part One (Principles for international registration of protocol information and results from human trials of health-related interventions) will be published in the supplement “Medicina Italia” of the first 2007 issue of Internal and Emergency Medicine as well in the Ottawa Statement website (http:// ottawagroup.ohri.ca). What’s the situation in Italy? Italy has been one of the first countries to legislate a universal compulsory trials’ registration. Through Local Ethic Committees (LECs) all trials are registered at the National Monitoring Centre for Clinical Trials (OsSC)9. Unfortunately not all the information is in the public domain; only funding bodies and the LECs have unrestricted access, while the public has access to only very selected information. This status quo does not comply with the principles and the policies of the above three initiatives. We urge the Ministry of Health to seriously consider revisiting the limitations in the amount of information that is available to the public to foster full transparency. In the meantime Italian researchers should duplicate their efforts, registering their trials within the OsSC and in an international open access register. We are aware that in the past two years many important goals have been achieved toward a global registration of and access to clinical trials. We are even more conscious that there is much room for improvement. Trial registers will only be useful if they increase the accessibility and transparency of evidence. The real test for trial registers is Cochrane’s corner