The Effect of Practitioner Empathy on Patient Satisfaction : A Systematic Review of Randomized Trials.

BACKGROUND: Practitioners who deliver enhanced empathy may improve patient satisfaction with care. Patient satisfaction is associated with positive patient outcomes ranging from medication adherence to survival. PURPOSE: To evaluate the effect of health care practitioner empathy on patient satisfaction, using a systematic review of randomized trials. DATA SOURCES: Ovid MEDLINE, CINAHL, PsycInfo, Cochrane Central Register of Controlled Trials, and Scopus to 23 October 2023. STUDY SELECTION: Randomized trials published in any language that evaluated the effect of empathy on improving patient satisfaction as measured on a validated patient satisfaction scale. DATA EXTRACTION: Data extraction, risk-of-bias assessments, and strength-of-evidence assessments were done by 2 independent reviewers. Disagreements were resolved through consensus. DATA SYNTHESIS: Fourteen eligible randomized trials (80 practitioners; 1986 patients) were included in the analysis. Five studies had high risk of bias, and 9 had some concerns about bias. The trials were heterogeneous in terms of geographic locations (North America, Europe, Asia, and Africa), settings (hospital and primary care), practitioner types (family and hospital physicians, anesthesiologists, nurses, psychologists, and caregivers), and type of randomization (individual patient or clustered by practitioner). Although all trials suggested a positive change in patient satisfaction, inadequate reporting hindered the ability to draw definitive conclusions about the overall effect size. LIMITATIONS: Heterogeneity in the way that empathy was delivered and patient satisfaction was measured and incomplete reporting leading to concerns about the certainty of the underpinning evidence. CONCLUSION: Various empathy interventions have been studied to improve patient satisfaction. Development, testing, and reporting of high-quality studies within well-defined contexts is needed to optimize empathy interventions that increase patient satisfaction. PRIMARY FUNDING SOURCE: Stoneygate Trust. (PROSPERO: CRD42023412981).

A survey of clinical empathy training at UK medical schools.

BACKGROUND: The benefits of enhancing practitioner empathy include better patient outcomes and improved job satisfaction for practitioners. Evidence suggests empathy can be taught and empathy is listed as an outcome for graduates in the General Medical Council requirements. Despite this, empathy training is not mandatory on medical school curricula and the extent to which medical students are given empathy-specific training is unknown. AIM: To conduct a survey of empathy training currently offered to medical students in UK medical schools. METHODS: An invitation to participate in an online survey was sent to all UK medical schools (n = 40). The survey was developed through a consultancy and pilot process to ensure validity and reliability. Questions explored what empathy-focused training is offered, and asked educators whether or not they believed that current provision of empathy training is sufficient. In parallel, medical school websites were searched to identify what information regarding empathy-focused training is described as being part of the degree course. Descriptive statistics were used to describe empathy training delivery from the results of the online materials survey and closed survey questions. Thematic analysis was used to explore free text comments. RESULTS: Response rate was 70% (28/40), with 28 medical schools included in the analysis. Twenty-six schools reported that their undergraduate curriculum included some form of empathy-focused training with variation in what, when and how this is delivered. Thematic analysis revealed two overarching themes with associated sub-themes: (i) empathy-focused training and development (considering where, when and how empathy training should be integrated); (ii) challenges presented by including empathy on the curriculum (considering the system, students and faculty). All schools agreed empathy training should be on the undergraduate curriculum. CONCLUSION: This is the first nationwide survey of empathy-focused training at UK medical schools. While some form of empathy-focused training appears to be provided on the undergraduate curriculum at most UK medical schools, empathy is rarely specifically assessed. Most medical educators do not feel their school does enough to promote empathy and the majority would like to offer more.

Why might medical student empathy change throughout medical school? a systematic review and thematic synthesis of qualitative studies.

BACKGROUND: Several studies suggest that medical student empathy declines throughout medical school. However, no studies have synthesised the evidence regarding why empathy declines. OBJECTIVE: To conduct a systematic review and thematic synthesis of qualitative studies investigating why student empathy may change throughout medical school. METHODS: We included any qualitative study that investigated why empathy might change during medical school. We searched the Medline, Scopus, CINAHL, ERIC, and APA PsycInfo databases for relevant studies. All databases were searched from their inception to 18 July 2022. We also searched the reference lists of the included studies and contacted experts to identify additional studies. We used the Joanna Briggs Institute tool to evaluate the risk of bias in the included studies. Overall confidence in our results was assessed using the Confidence in the Evidence from Reviews of Qualitative research (CERQual) approach. We used thematic methods to synthesise our findings. RESULTS: Our searches yielded 2523 records, and 16 studies involving a total of 771 students were eligible for analysis. Most studies (n = 11) were from Europe or North America. The descriptive themes and sub-themes were identified for each study. Increased complexity in patients and their diseases, together with the 'hidden curriculum' (including a stressful workload, prioritisation of biomedical knowledge, and (sometimes) poor role models), led to student adaptations, such as cynicism and desensitisation. Students' prior lives and professional experiences appeared to exacerbate the decline in empathy. However, there were bias concerns for most of the included studies. DISCUSSION: Many of the included studies included were small, and some did not include demographic participant data. Given the likely benefits of providing empathic care for patients and practitioners, medical education interventions should focus on developing an 'empathic hidden curriculum' that mitigates the decline in medical student empathy. TRIAL REGISTRATION: A protocol for this systematic review was submitted for registration with the International Prospective Register of Systematic Reviews (PROSPERO) on 28 July 2022 (registration number CRD42022347856).

Teaching an empathy-focused approach to difficult consultations: a pilot session and co-production evaluation workshop.

BACKGROUND: Patients who are annoyed, upset, angry or uncooperative may be categorised as having behavioural problems, shifting the blame from healthcare providers to patients. This can exacerbate the problem. Adopting an empathic approach to such consultations can reduce anger and frustration and improve patient care. APPROACH: A pilot teaching session was introduced to the second year of the medical degree at Leicester Medical School with the aim of preparing students to deal with difficult consultations and helping them to understand the impact of empathy in such situations. The teaching involved the use of prior reading, videos and simulated patients acting the role of angry and frustrated patients. It was delivered to groups of 8 students by a team of 20 GP tutors. Approximately 300 second year medical students took part in the session. EVALUATION: Ninety per cent of students felt they had a better understanding of how an empathic approach could help in difficult consultations. Most GP tutors also felt better prepared to deal with difficult consultations because of teaching the session. Following the initial evaluation, a co-production workshop was convened comprising of tutors, students and patient representatives to review the teaching materials and evaluation. Potential improvements to the session were identified. CONCLUSION: We were able to deliver a successful pilot session that improved students' understanding of the skills needed and had a positive impact on GP tutors involved in the session. A subsequent co-production workshop identified key strategies to improve the session for future years.

Duration of Protection After Vaccination Against Yellow Fever: A Systematic Review and Meta-Analysis.

The duration of protection after a single dose of yellow fever vaccine is a matter of debate. To summarize the current knowledge, we performed a systematic literature review and meta-analysis. Studies on the duration of protection after 1 and ≥2 vaccine doses were reviewed. Data were stratified by time since vaccination. In our meta-analysis, we used random-effects models. We identified 36 studies from 20 countries, comprising more than 17 000 participants aged 6 months to 85 years. Among healthy adults and children, pooled seroprotection rates after single vaccination dose were close to 100% by 3 months and remained high in adults for 5 to 10 years. In children vaccinated before age 2 years, the seroprotection rate was 52% within 5 years after primary vaccination. For immunodeficient persons, data indicate relevant waning. The extent of waning of seroprotection after yellow fever vaccination depends on age and immune status at primary vaccination.

How do they add up? The interaction between the placebo and treatment effect: A systematic review.

AIM: The placebo effect and the specific effect are often thought to add up (additive model). Whether additivity holds can dramatically influence the external validity of a trial. This assumption of additivity was tested by Kleijnen et al in 1994 but the data produced since then have not been synthetized. In this review, we aimed to systematically review the literature to determine whether additivity held. METHODS: We searched Medline and PsychInfo up to 10 January 2019. Studies using the balanced placebo design (BPD), testing two different strengths of placebos, were included. The presence of interaction was evaluated by comparing each group in the BPD with analysis of variance or covariance. RESULTS: Thirty studies were included and the overall risk of bias was high: four found evidence of additivity and 16 studies found evidence of interaction (seven had evidence of positive additivity). CONCLUSION: Evidence of additivity between placebo and specific features of treatments was rare in included studies. We suggest interventions for placebo-sensitive ailments should be tested in trials designed to take interactions seriously once an exploratory RCTs has proven their efficacy with sufficient internal validity.

The evidence for cognitive behavioural therapy in any condition, population or context: a meta-review of systematic reviews and panoramic meta-analysis.

The majority of psychological treatment research is dedicated to investigating the effectiveness of cognitive behavioural therapy (CBT) across different conditions, population and contexts. We aimed to summarise the current systematic review evidence and evaluate the consistency of CBT's effect across different conditions. We included reviews of CBT randomised controlled trials in any: population, condition, format, context, with any type of comparator and published in English. We searched DARE, Cochrane, MEDLINE, EMBASE, PsycINFO, CINAHL, CDAS, and OpenGrey between 1992 and January 2019. Reviews were quality assessed, their data extracted and summarised. The effects upon health-related quality of life (HRQoL) were pooled, within-condition groups. If the across-condition heterogeneity was I2 < 75%, we pooled effects using a random-effect panoramic meta-analysis. We summarised 494 reviews (221 128 participants), representing 14/20 physical and 13/20 mental conditions (World Health Organisation's International Classification of Diseases). Most reviews were lower-quality (351/494), investigated face-to-face CBT (397/494), and in adults (378/494). Few reviews included trials conducted in Asia, South America or Africa (45/494). CBT produced a modest benefit across-conditions on HRQoL (standardised mean difference 0.23; 95% confidence intervals 0.14-0.33, I2 = 32%). The effect's associated prediction interval -0.05 to 0.50 suggested CBT will remain effective in conditions for which we do not currently have available evidence. While there remain some gaps in the completeness of the evidence base, we need to recognise the consistent evidence for the general benefit which CBT offers.

What Should Clinicians Tell Patients about Placebo and Nocebo Effects? Practical Considerations Based on Expert Consensus.

INTRODUCTION: Clinical and laboratory studies demonstrate that placebo and nocebo effects influence various symptoms and conditions after the administration of both inert and active treatments. OBJECTIVE: There is an increasing need for up-to-date recommendations on how to inform patients about placebo and nocebo effects in clinical practice and train clinicians how to disclose this information. METHODS: Based on previous clinical recommendations concerning placebo and nocebo effects, a 3-step, invitation-only Delphi study was conducted among an interdisciplinary group of internationally recognized experts. The study consisted of open- and closed-ended survey questions followed by a final expert meeting. The surveys were subdivided into 3 parts: (1) informing patients about placebo effects, (2) informing patients about nocebo effects, and (3) training clinicians how to communicate this information to the patients. RESULTS: There was consensus that communicating general information about placebo and nocebo effects to patients (e.g., explaining their role in treatment) could be beneficial, but that such information needs to be adjusted to match the specific clinical context (e.g., condition and treatment). Experts also agreed that training clinicians to communicate about placebo and nocebo effects should be a regular and integrated part of medical education that makes use of multiple formats, including face-to-face and online modalities. CONCLUSIONS: The current 3-step Delphi study provides consensus-based recommendations and practical considerations for disclosures about placebo and nocebo effects in clinical practice. Future research is needed on how to optimally tailor information to specific clinical conditions and patients' needs, and on developing standardized disclosure training modules for clinicians.

Unethical informed consent caused by overlooking poorly measured nocebo effects.

Unlike its friendly cousin the placebo effect, the nocebo effect (the effect of expecting a negative outcome) has been almost ignored. Epistemic and ethical confusions related to its existence have gone all but unnoticed. Contrary to what is often asserted, adverse events following from taking placebo interventions are not necessarily nocebo effects; they could have arisen due to natural history. Meanwhile, ethical informed consent (in clinical trials and clinical practice) has centred almost exclusively on the need to inform patients about intervention risks with patients to preserve their autonomy. Researchers have failed to consider the harm caused by the way in which the information is conveyed. In this paper, I argue that the magnitude of nocebo effects must be measured using control groups consisting of untreated patients. And, because the nocebo effect can produce harm, the principle of non-maleficence must be taken into account alongside autonomy when obtaining (ethical) informed consent and communicating intervention risks with patients.

TIDieR-Placebo: A guide and checklist for reporting placebo and sham controls.

BACKGROUND: Placebo or sham controls are the standard against which the benefits and harms of many active interventions are measured. Whilst the components and the method of their delivery have been shown to affect study outcomes, placebo and sham controls are rarely reported and often not matched to those of the active comparator. This can influence how beneficial or harmful the active intervention appears to be. Without adequate descriptions of placebo or sham controls, it is difficult to interpret results about the benefits and harms of active interventions within placebo-controlled trials. To overcome this problem, we developed a checklist and guide for reporting placebo or sham interventions. METHODS AND FINDINGS: We developed an initial list of items for the checklist by surveying experts in placebo research (n = 14). Because of the diverse contexts in which placebo or sham treatments are used in clinical research, we consulted experts in trials of drugs, surgery, physiotherapy, acupuncture, and psychological interventions. We then used a multistage online Delphi process with 53 participants to determine which items were deemed to be essential. We next convened a group of experts and stakeholders (n = 16). Our main output was a modification of the existing Template for Intervention Description and Replication (TIDieR) checklist; this allows the key features of both active interventions and placebo or sham controls to be concisely summarised by researchers. The main differences between TIDieR-Placebo and the original TIDieR are the explicit requirement to describe the setting (i.e., features of the physical environment that go beyond geographic location), the need to report whether blinding was successful (when this was measured), and the need to present the description of placebo components alongside those of the active comparator. CONCLUSIONS: We encourage TIDieR-Placebo to be used alongside TIDieR to assist the reporting of placebo or sham components and the trials in which they are used.

Improving Empathy in Healthcare Consultations-a Secondary Analysis of Interventions.

A recent systematic review of randomised trials suggested that empathic communication improves patient health outcomes. However, the methods for training healthcare practitioners (medical professionals; HCPs) in empathy and the empathic behaviours demonstrated within the trials were heterogeneous, making the evidence difficult to implement in routine clinical practice. In this secondary analysis of seven trials in the review, we aimed to identify (1) the methods used to train HCPs, (2) the empathy behaviours they were trained to perform and (3) behaviour change techniques (BCTs) used to encourage the adoption of those behaviours. This detailed understanding of interventions is necessary to inform implementation in clinical practice. We conducted a content analysis of intervention descriptions, using an inductive approach to identify training methods and empathy behaviours and a deductive approach to describe the BCTs used. The most commonly used methods to train HCPs to enhance empathy were face-to-face training (n = 5), role-playing (n = 3) and videos (self or model; n = 3). Duration of training was varied, with both long and short training having high effect sizes. The most frequently targeted empathy behaviours were providing explanations of treatment (n = 5), providing non-specific empathic responses (e.g. expressing understanding) and displaying a friendly manner and using non-verbal behaviours (e.g. nodding, leaning forward, n = 4). The BCT most used to encourage HCPs to adopt empathy behaviours was "Instruction on how to perform behaviour" (e.g. a video demonstration, n = 5), followed by "Credible source" (e.g. delivered by a psychologist, n = 4) and "Behavioural practice" (n = 3 e.g. role-playing). We compared the effect sizes of studies but could not extrapolate meaningful conclusions due to high levels of variation in training methods, empathy skills and BCTs. Moreover, the methods used to train HCPs were often poorly described which limits study replication and clinical implementation. This analysis of empathy training can inform future research, intervention reporting standards and clinical practice.

European Headache Federation recommendations for placebo and nocebo terminology.

BACKGROUND AND AIM: Despite recent publications, practitioners remain unfamiliar with the current terminology related to the placebo and nocebo phenomena observed in clinical trials and practice, nor with the factors that modulate them. To cover the gap, the European Headache Federation appointed a panel of experts to clarify the terms associated with the use of placebo in clinical trials. METHODS: The working group identified relevant questions and agreed upon recommendations. Because no data were required to answer the questions, the GRADE approach was not applicable, and thus only expert opinion was provided according to an amended Delphi method. The initial 12 topics for discussion were revised in the opinion of the majority of the panelists, and after a total of 6 rounds of negotiations, the final agreement is presented. RESULTS/RECOMMENDATIONS: Two primary and mechanism-based recommendations are provided for the results of clinical trials: [1] to distinguish the placebo or nocebo response from the placebo or nocebo effect; and [2] for any favorable outcome observed after placebo administration, the term "placebo response" should be used, and for any unfavorable outcome recorded after placebo administration, the term "nocebo response" should be used (12 out of 17 panelists agreed, 70.6% agreement). The placebo or nocebo responses are attributed to a set of factors including those that are related to the medical condition (e.g. natural history, random comorbidities, etc.), along with idiosyncratic ones, in which the placebo or nocebo effects are attributed to idiosyncratic, or nonspecific mechanisms, exclusively (e.g. expectation, conditioning, observational learning etc.). To help investigators and practitioners, the panel summarized a list of environmental factors and idiosyncratic dynamics modulating placebo and nocebo effects. Some of them are modifiable, and investigators or physicians need to know about them in order to modify these factors appropriately to improve treatment. One secondary recommendation addresses the use of the terms "placebo" and "nocebo" ("placebos" and "nocebos" in plural), which refer to the triggers of the placebo/nocebo effects or responses, respectively, and which are inert agents or interventions that should not be confused with the placebo/nocebo responses or effects themselves (all panelists agreed, 100% agreement). CONCLUSION: The working group recommends distinguishing the term response from effect to describe health changes from before to after placebo application and to distinguish the terms placebo(s) or nocebo(s) from the health consequences that they cause (placebo/nocebo responses or effects).

Inadequate description of placebo and sham controls in a systematic review of recent trials.

BACKGROUND: Poorly described placebo/sham controls make it difficult to appraise active intervention benefits and harms. The 12-item Template for Intervention Description and Replication (TIDieR) checklist was developed to improve the reporting of active interventions. The extent to which TIDieR has been used to improve description of placebo or sham control is not known. MATERIALS AND METHODS: We systematically identified and examined all placebo/sham-controlled randomised trials published in 2018 in the top six general medical journals. We reported how many of the TIDieR checklist items were used to describe the placebo/sham control(s). We supplemented this with a sample of 100 placebo/sham-controlled trials from any journal and searched Google Scholar to identify placebo/sham-controlled trials citing TIDieR. RESULTS: We identified 94 placebo/sham-controlled trials published in the top journals in 2018. None reported using TIDieR, and none reported placebo or sham components completely. On average eight TIDieR items were addressed, with placebo/sham control name (100%) and when and how much was administered (97.9%) most commonly reported. Some items (rationale, 8.5%, whether there were modifications, 25.5%) were less often reported. In our sample of less well-cited journals, reporting was poorer (average of six items) and followed a similar pattern. Since TIDieR's first publication, six placebo-controlled trials have cited it according to Google Scholar. Two of these used the checklist to describe placebo controls; neither one completely desribed the placebo intervention. CONCLUSIONS: Placebo and sham controls are poorly described within randomised trials, and TIDieR is rarely used to guide these descriptions. We recommend developing guidelines to promote better descriptions of placebo/sham control components within clinical trials.

Exploring the Asymmetrical Relationship Between the Power of Finance Bias and Evidence.

Financial conflicts of interest can influence the design, conduct, and dissemination of medical trials. In attempting to resist "finance bias," critics and proponents of evidence-based medicine (EBM) and its precursors have largely focused on trying to improve evidence. These efforts have led to successes ranging from the 1962 Kefauver-Harris amendments to the US Federal Drug and Cosmetic Act of 1938 to recent recommendations that all trials be published. However, there are two problems with the strategy of trying to improve evidence as a buffer against finance bias. First, without political teeth, rules of evidence can be ignored with relative impunity. This is because, as sociologist Bent Flyvbjerg has pointed out, there is an asymmetry between power (of finance bias) and rationality (evidence), tending towards victory of power in an open confrontation. Second, by improving the way evidence is produced, the process has become more expensive, and thus more susceptible to influence by finance bias. Unless they address the powers behind finance bias directly, critics and proponents may be doomed to lose the war against finance bias, even if they win some battles. For EBM to be effective, the power of finance bias influencing the production and dissemination of evidence needs to be addressed as a priority. This is starting to happen, with initiatives such as the AllTrials campaign, which identifies and exposes unpublished trials. On the other hand, there are reasons to be less optimistic, as Cochrane, the most trusted source of evidence, has become more susceptible to stronger influences from industry.

Implications of Placebo and Nocebo Effects for Clinical Practice: Expert Consensus.

BACKGROUND: Placebo and nocebo effects occur in clinical or laboratory medical contexts after administration of an inert treatment or as part of active treatments and are due to psychobiological mechanisms such as expectancies of the patient. Placebo and nocebo studies have evolved from predominantly methodological research into a far-reaching interdisciplinary field that is unravelling the neurobiological, behavioural and clinical underpinnings of these phenomena in a broad variety of medical conditions. As a consequence, there is an increasing demand from health professionals to develop expert recommendations about evidence-based and ethical use of placebo and nocebo effects for clinical practice. METHODS: A survey and interdisciplinary expert meeting by invitation was organized as part of the 1st Society for Interdisciplinary Placebo Studies (SIPS) conference in 2017. Twenty-nine internationally recognized placebo researchers participated. RESULTS: There was consensus that maximizing placebo effects and minimizing nocebo effects should lead to better treatment outcomes with fewer side effects. Experts particularly agreed on the importance of informing patients about placebo and nocebo effects and training health professionals in patient-clinician communication to maximize placebo and minimize nocebo effects. CONCLUSIONS: The current paper forms a first step towards developing evidence-based and ethical recommendations about the implications of placebo and nocebo research for medical practice, based on the current state of evidence and the consensus of experts. Future research might focus on how to implement these recommendations, including how to optimize conditions for educating patients about placebo and nocebo effects and providing training for the implementation in clinical practice.

Empirical evidence against placebo controls.

The revised Declaration of Helsinki allows placebo-controlled trials to be used even when there is an established therapy, provided there are adequate 'methodological' reasons for doing so. This seems to violate the principle of beneficence: where there is an established therapy, physicians treating patients with a placebo are withholding a known effective therapy. Because of this problem, we hypothesised that clinical researchers may be unwilling to risk violating the principle of beneficence and employ placebo-controlled trials in cases where there is an established therapy. In this paper, we began to investigate this hypothesis. After summarising the arguments for and against using placebo controls in clinical practice, we exploredthe extent to which placebo-controlled trials are used in cases where there is an established therapy. To do this, we conducted as systematic search for all placebo-controlled trials published in 2015 in the five highest impact general medical journals. We identified 70 placebo-controlled trials. Of these, 66 were for indications where there was no established effective therapy. Only four used a placebo control in spite of there being an available effective therapy. The infrequent use of placebo controlled trials where established therapy exists highlights a seeming discrepancy between what the Declaration of Helsinki allows and what clinical investigators believe to be ethically acceptable. The evidence presented in this paper suggests that the Declaration of Helsinki be reconsidered, and perhaps revised, in light of actual practice.

Point-of-care testing in UK primary care: a survey to establish clinical needs.

BACKGROUND: A number of point-of-care diagnostic tests are commercially available in the UK, however, not much is known regarding GPs' desire for these tests or the clinical areas of interest. OBJECTIVE: We sought to establish for which conditions point-of-care tests (POCTs) would be most helpful to UK GPs for diagnosis, reduction of referrals, and monitoring of chronic conditions. METHODS: A total of 1635 regionally representative GPs were invited to complete an online cross-sectional survey between 31 September and 16 October 2012. RESULTS: A total of 1109 (68%) GPs responded to the survey. The most frequently cited conditions were urinary tract infections for diagnosis (47% of respondents), pulmonary embolism/deep vein thrombosis for referral reduction (47%) and international normalized ratio/anticoagulation for monitoring (49%). CONCLUSIONS: This survey has identified the conditions for which UK GPs would find POCTs most helpful. Comments by respondents suggest that quite radical system-level adjustments will be required to allow primary care clinicians to capitalize on the potential benefits of POCTs.

The importance of values in evidence-based medicine.

BACKGROUND: Evidence-based medicine (EBM) has always required integration of patient values with 'best' clinical evidence. It is widely recognized that scientific practices and discoveries, including those of EBM, are value-laden. But to date, the science of EBM has focused primarily on methods for reducing bias in the evidence, while the role of values in the different aspects of the EBM process has been almost completely ignored. DISCUSSION: In this paper, we address this gap by demonstrating how a consideration of values can enhance every aspect of EBM, including: prioritizing which tests and treatments to investigate, selecting research designs and methods, assessing effectiveness and efficiency, supporting patient choice and taking account of the limited time and resources available to busy clinicians. Since values are integral to the practice of EBM, it follows that the highest standards of EBM require values to be made explicit, systematically explored, and integrated into decision making. Through 'values based' approaches, EBM's connection to the humanitarian principles upon which it was founded will be strengthened.

Neuraminidase inhibitors for preventing and treating influenza in adults and children.

BACKGROUND: Neuraminidase inhibitors (NIs) are stockpiled and recommended by public health agencies for treating and preventing seasonal and pandemic influenza. They are used clinically worldwide. OBJECTIVES: To describe the potential benefits and harms of NIs for influenza in all age groups by reviewing all clinical study reports of published and unpublished randomised, placebo-controlled trials and regulatory comments. SEARCH METHODS: We searched trial registries, electronic databases (to 22 July 2013) and regulatory archives, and corresponded with manufacturers to identify all trials. We also requested clinical study reports. We focused on the primary data sources of manufacturers but we checked that there were no published randomised controlled trials (RCTs) from non-manufacturer sources by running electronic searches in the following databases: the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, MEDLINE (Ovid), EMBASE, Embase.com, PubMed (not MEDLINE), the Database of Reviews of Effects, the NHS Economic Evaluation Database and the Health Economic Evaluations Database. SELECTION CRITERIA: Randomised, placebo-controlled trials on adults and children with confirmed or suspected exposure to naturally occurring influenza. DATA COLLECTION AND ANALYSIS: We extracted clinical study reports and assessed risk of bias using purpose-built instruments. We analysed the effects of zanamivir and oseltamivir on time to first alleviation of symptoms, influenza outcomes, complications, hospitalisations and adverse events in the intention-to-treat (ITT) population. All trials were sponsored by the manufacturers. MAIN RESULTS: We obtained 107 clinical study reports from the European Medicines Agency (EMA), GlaxoSmithKline and Roche. We accessed comments by the US Food and Drug Administration (FDA), EMA and Japanese regulator. We included 53 trials in Stage 1 (a judgement of appropriate study design) and 46 in Stage 2 (formal analysis), including 20 oseltamivir (9623 participants) and 26 zanamivir trials (14,628 participants). Inadequate reporting put most of the zanamivir studies and half of the oseltamivir studies at a high risk of selection bias. There were inadequate measures in place to protect 11 studies of oseltamivir from performance bias due to non-identical presentation of placebo. Attrition bias was high across the oseltamivir studies and there was also evidence of selective reporting for both the zanamivir and oseltamivir studies. The placebo interventions in both sets of trials may have contained active substances. Time to first symptom alleviation. For the treatment of adults, oseltamivir reduced the time to first alleviation of symptoms by 16.8 hours (95% confidence interval (CI) 8.4 to 25.1 hours, P < 0.0001). This represents a reduction in the time to first alleviation of symptoms from 7 to 6.3 days. There was no effect in asthmatic children, but in otherwise healthy children there was (reduction by a mean difference of 29 hours, 95% CI 12 to 47 hours, P = 0.001). Zanamivir reduced the time to first alleviation of symptoms in adults by 0.60 days (95% CI 0.39 to 0.81 days, P < 0.00001), equating to a reduction in the mean duration of symptoms from 6.6 to 6.0 days. The effect in children was not significant. In subgroup analysis we found no evidence of a difference in treatment effect for zanamivir on time to first alleviation of symptoms in adults in the influenza-infected and non-influenza-infected subgroups (P = 0.53). Hospitalisations. Treatment of adults with oseltamivir had no significant effect on hospitalisations: risk difference (RD) 0.15% (95% CI -0.78 to 0.91). There was also no significant effect in children or in prophylaxis. Zanamivir hospitalisation data were unreported. Serious influenza complications or those leading to study withdrawal. In adult treatment trials, oseltamivir did not significantly reduce those complications classified as serious or those which led to study withdrawal (RD 0.07%, 95% CI -0.78 to 0.44), nor in child treatment trials; neither did zanamivir in the treatment of adults or in prophylaxis. There were insufficient events to compare this outcome for oseltamivir in prophylaxis or zanamivir in the treatment of children. Pneumonia. Oseltamivir significantly reduced self reported, investigator-mediated, unverified pneumonia (RD 1.00%, 95% CI 0.22 to 1.49); number needed to treat to benefit (NNTB) = 100 (95% CI 67 to 451) in the treated population. The effect was not significant in the five trials that used a more detailed diagnostic form for pneumonia. There were no definitions of pneumonia (or other complications) in any trial. No oseltamivir treatment studies reported effects on radiologically confirmed pneumonia. There was no significant effect on unverified pneumonia in children. There was no significant effect of zanamivir on either self reported or radiologically confirmed pneumonia. In prophylaxis, zanamivir significantly reduced the risk of self reported, investigator-mediated, unverified pneumonia in adults (RD 0.32%, 95% CI 0.09 to 0.41); NNTB = 311 (95% CI 244 to 1086), but not oseltamivir. Bronchitis, sinusitis and otitis media. Zanamivir significantly reduced the risk of bronchitis in adult treatment trials (RD 1.80%, 95% CI 0.65 to 2.80); NNTB = 56 (36 to 155), but not oseltamivir. Neither NI significantly reduced the risk of otitis media and sinusitis in both adults and children. Harms of treatment. Oseltamivir in the treatment of adults increased the risk of nausea (RD 3.66%, 95% CI 0.90 to 7.39); number needed to treat to harm (NNTH) = 28 (95% CI 14 to 112) and vomiting (RD 4.56%, 95% CI 2.39 to 7.58); NNTH = 22 (14 to 42). The proportion of participants with four-fold increases in antibody titre was significantly lower in the treated group compared to the control group (RR 0.92, 95% CI 0.86 to 0.97, I(2) statistic = 0%) (5% absolute difference between arms). Oseltamivir significantly decreased the risk of diarrhoea (RD 2.33%, 95% CI 0.14 to 3.81); NNTB = 43 (95% CI 27 to 709) and cardiac events (RD 0.68%, 95% CI 0.04 to 1.0); NNTB = 148 (101 to 2509) compared to placebo during the on-treatment period. There was a dose-response effect on psychiatric events in the two oseltamivir "pivotal" treatment trials, WV15670 and WV15671, at 150 mg (standard dose) and 300 mg daily (high dose) (P = 0.038). In the treatment of children, oseltamivir induced vomiting (RD 5.34%, 95% CI 1.75 to 10.29); NNTH = 19 (95% CI 10 to 57). There was a significantly lower proportion of children on oseltamivir with a four-fold increase in antibodies (RR 0.90, 95% CI 0.80 to 1.00, I(2) = 0%). Prophylaxis. In prophylaxis trials, oseltamivir and zanamivir reduced the risk of symptomatic influenza in individuals (oseltamivir: RD 3.05% (95% CI 1.83 to 3.88); NNTB = 33 (26 to 55); zanamivir: RD 1.98% (95% CI 0.98 to 2.54); NNTB = 51 (40 to 103)) and in households (oseltamivir: RD 13.6% (95% CI 9.52 to 15.47); NNTB = 7 (6 to 11); zanamivir: RD 14.84% (95% CI 12.18 to 16.55); NNTB = 7 (7 to 9)). There was no significant effect on asymptomatic influenza (oseltamivir: RR 1.14 (95% CI 0.39 to 3.33); zanamivir: RR 0.97 (95% CI 0.76 to 1.24)). Non-influenza, influenza-like illness could not be assessed due to data not being fully reported. In oseltamivir prophylaxis studies, psychiatric adverse events were increased in the combined on- and off-treatment periods (RD 1.06%, 95% CI 0.07 to 2.76); NNTH = 94 (95% CI 36 to 1538) in the study treatment population. Oseltamivir increased the risk of headaches whilst on treatment (RD 3.15%, 95% CI 0.88 to 5.78); NNTH = 32 (95% CI 18 to 115), renal events whilst on treatment (RD 0.67%, 95% CI -2.93 to 0.01); NNTH = 150 (NNTH 35 to NNTB > 1000) and nausea whilst on treatment (RD 4.15%, 95% CI 0.86 to 9.51); NNTH = 25 (95% CI 11 to 116). AUTHORS' CONCLUSIONS: Oseltamivir and zanamivir have small, non-specific effects on reducing the time to alleviation of influenza symptoms in adults, but not in asthmatic children. Using either drug as prophylaxis reduces the risk of developing symptomatic influenza. Treatment trials with oseltamivir or zanamivir do not settle the question of whether the complications of influenza (such as pneumonia) are reduced, because of a lack of diagnostic definitions. The use of oseltamivir increases the risk of adverse effects, such as nausea, vomiting, psychiatric effects and renal events in adults and vomiting in children. The lower bioavailability may explain the lower toxicity of zanamivir compared to oseltamivir. The balance between benefits and harms should be considered when making decisions about use of both NIs for either the prophylaxis or treatment of influenza. The influenza virus-specific mechanism of action proposed by the producers does not fit the clinical evidence.