Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline.

CLINICAL QUESTION: What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice. CURRENT PRACTICE: Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing. RECOMMENDATION: The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying to become pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or young adults (such as those ≤30 years old). HOW THIS GUIDELINE WAS CREATED: A guideline panel including patients, clinicians, and methodologists produced this recommendation in adherence with standards for trustworthy guidelines using the GRADE approach. THE EVIDENCE: The systematic review included 21 trials with 2192 participants. For adults with SCH, thyroid hormones consistently demonstrate no clinically relevant benefits for quality of life or thyroid related symptoms, including depressive symptoms, fatigue, and body mass index (moderate to high quality evidence). Thyroid hormones may have little or no effect on cardiovascular events or mortality (low quality evidence), but harms were measured in only one trial with few events at two years' follow-up. UNDERSTANDING THE RECOMMENDATION: The panel concluded that almost all adults with SCH would not benefit from treatment with thyroid hormones. Other factors in the strong recommendation include the burden of lifelong management and uncertainty on potential harms. Instead, clinicians should monitor the progression or resolution of the thyroid dysfunction in these adults. Recommendations are made actionable for clinicians and their patients through visual overviews. These provide the relative and absolute benefits and harms of thyroid hormones in multilayered evidence summaries and decision aids available in MAGIC (https://app.magicapp.org/) to support shared decisions and adaptation of this guideline.

Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline

What are the benefits and harms of thyroid hormones for adults with subclinical hypothyroidism (SCH)? This guideline was triggered by a recent systematic review of randomised controlled trials, which could alter practice. Current guidelines tend to recommend thyroid hormones for adults with thyroid stimulating hormone (TSH) levels >10 mIU/L and for people with lower TSH values who are young, symptomatic, or have specific indications for prescribing. The guideline panel issues a strong recommendation against thyroid hormones in adults with SCH (elevated TSH levels and normal free T4 (thyroxine) levels). It does not apply to women who are trying tobecome pregnant or patients with TSH >20 mIU/L. It may not apply to patients with severe symptoms or youngadults (such as those ≤30 years old).

Patient versus general population health state valuations: a case study of non-specific low back pain.

PURPOSE: The purpose of this study was twofold: (1) to compare non-specific low back pain (LBP) patients' health state valuations with those of the general population, and (2) to explore how aspects of health-related quality of life as measured by the EQ-5D-3L impact non-specific LBP patient valuations. METHODS: Data were used of a randomized controlled trial, including 483 non-specific LBP patients. Outcomes included the EQ-VAS and the EQ-5D-3L. Patient valuations were derived from the EQ-VAS. Population valuations were derived from the EQ-5D-3L using a Dutch VAS-based tariff. The difference between patient and population valuations was assessed using t tests. An OLS linear regression model was constructed to explore how various aspects of health-related quality of life as measured by the ED-5D-3L impact non-specific LBP patient valuations. RESULTS: Non-specific LBP patients valued their health states 0.098 (95% CI 0.082-0.115) points higher than the general population. Only 22.2% of the variance in patient valuations was explained by the patients' EQ-5D-3L health states (R 2 = 0.222). Non-specific LBP patients gave the most weight to the anxiety/depression dimension. CONCLUSIONS: This study demonstrated that non-specific LBP patients value their health states higher than members of the general population and that the choice of valuation method could have important implications for cost-effectiveness analyses and thus for clinical practice.

Practitioner review: evidence-based practice guidelines on alcohol and drug misuse among adolescents: a systematic review.

BACKGROUND: Context-specific evidence-based guidelines on how to prevent and treat substance misuse among adolescents are currently lacking in many countries. Due to the time consuming nature of de novo guideline development, the ADAPTE collaboration introduced a methodology to adapt existing guidelines to a local context. An important step in this method is a systematic review to identify relevant high-quality evidence-based guidelines. This study describes the results of this step for the development of guidelines on adolescent alcohol and drug misuse in Belgium. METHODS: Rigorous systematic review methodology was used. This included searches of electronic databases (Medline, Embase, Cinahl, PsychInfo, and ERIC in June 2011), websites of relevant organizations, and reference lists of key publications. Experts in the field were also contacted. Included were Dutch, English, French, or German evidence-based practice guidelines from 2006 or later on the prevention, screening, assessment, or treatment of alcohol or illicit drug misuse in persons aged 12-18 years. Two independent reviewers assessed the quality of the guidelines using the AGREE II (Appraisal of Guidelines for Research and Evaluation) instrument. SCOPE: This overview provides a framework of current knowledge in adolescent alcohol and drug misuse prevention and treatment. RESULTS: This systematic review identified 32 relevant evidence-based guidelines on substance misuse among adolescents. Nine guidelines were judged to be of high quality; of which four had recommendations specifically on adolescents: one on school-based prevention, one on substance misuse prevention in vulnerable young people and two on alcohol misuse with specific sections for the adolescent population. There were few commonalities as guidelines focused on different target groups, professional disciplines and type and level of substance misuse. Evidence to support the recommendations was sparse, and many recommendations were based on expert consensus or on studies among adults. Also, the link between evidence and recommendations was often unclear. CONCLUSIONS: There are a substantial number of guidelines addressing substance misuse in adolescents. However, only four high-quality guidelines included recommendations specific for adolescents. The current level of evidence that underpins the recommendations in these high-quality guidelines is low.

Evidence-based medicine in anesthesiology.

Two decades ago, Evidence-Based Medicine (EBM) was introduced to improve the quality of medical care. Using EBM in practice can be seen as a cyclic process consisting of 5 steps. This paper explains how to apply these steps in anesthesiology. The EBM cycle involves: 1. Asking a relevant clinical question, 2. Finding evidence to answer the question, 3. Appraising the evidence, 4. Applying the findings to practice, which means integrating evidence, clinical experience and patient preferences, and 5. Reviewing these steps. Applying EMB requires effort and certain skills, for example searching for evidence and appraising the quality of the evidence. Also important is a reflective attitude towards the practitioner's own practice. This paper aims at encouraging anesthesiologists to develop such skills and to implement the steps of EBM in their daily practice.

Can morphine still be considered to be the standard for treating chronic pain? A systematic review including pair-wise and network meta-analyses.

OBJECTIVE: For chronic pain treatment many health care authorities consider morphine to be the reference standard for strategic decisions in pain therapy. Although morphine's effectiveness is clear and its cost is low, it's unclear whether morphine should remain the first choice or reference treatment. RESEARCH DESIGN AND METHODS: We performed a systematic review to evaluate the evidence available to support the position of morphine as the reference standard for step III opioids based on efficacy and tolerability outcomes. RESULTS: The search yielded 5,675 titles and 56 studies were included. Considerable heterogeneity precluded pair-wise meta-analysis on change of pain intensity and no difference between morphine and other opioids were found for tolerability outcomes. The network meta-analysis showed no statistically significant difference in change of pain intensity between morphine and oxycodone, methadone and oxymorphone. Compared to morphine, patients using buprenorphine are more likely to discontinue treatment due to lack of effect (OR 2.32, 95% CI 1.37 to 3.95). Patients using methadone are more likely to discontinue due to adverse events (OR 3.09, 95% CI 1.14 to 8.36), whereas this risk is decreased for patients using fentanyl (OR 0.29, 95% CI 0.17 to 0.50) or buprenorphine (OR 0.30, 95% CI 0.16 to 0.53). The most important limitation of this review is that the included studies are heterogeneous with regard to study population and intervention, which may affect the pooled effect estimates. The main strength is that we only included parallel RCTs, the strongest design for intervention studies. CONCLUSIONS: The current evidence is moderate, both in respect to the number of directly comparative studies and in the quality of reporting of these studies. No clear superiority in efficacy and tolerability of morphine over other opioids was found in pair-wise and network analyses. Based on these results, a justification for the placement of morphine as the reference standard for the treatment of severe chronic pain cannot be supported.

Epidemiology of chronic pain and its treatment in The Netherlands.

BACKGROUND: Chronic pain is common; however, good epidemiological data are scarce. Such information can help all the involved stakeholders to make responsible decisions about health budgets and prioritisation. This study aims to provide best-evidence epidemiological information about chronic pain in the Netherlands. METHODS: We performed a systematic search which yielded 16,619 references, 119 Dutch studies were relevant. We selected at least three studies per question that provided the most recent, representative and valid data. RESULTS: The prevalence of moderate to severe general chronic pain among Dutch adults was estimated at 18%. This prevalence was 27% and 55% for any cancer pain. Up to 74% of patients with general or non-cancer chronic pain get treated; this percentage is little higher for patients with cancer pain. A substantial proportion of the patients receive drug treatment for their pain, mainly NSAIDs, but also non-pharmacological interventions for pain are being used. Up to 43% of the chronic non-cancer pain patients report not receiving treatment and up to 79% of the patients believe their pain is inadequately treated. All studies reported a detrimental effect of chronic pain on quality of life, activities of daily living and mental health. Chronic pain is also associated with direct and indirect medical costs, and patients may have decreased income and additional out-of pocket expenses. CONCLUSION: Chronic pain occur s frequently, has a negative impact on the patient and society and treatment may not always be adequate. Chronic pain should be seen as an important public health problem deserving more attention of Dutch healthcare workers and policy makers.

[Procedures and methods of benefit assessments for medicines in Germany]. / Verfahrensweisen und Methoden zur Nutzenbewertung von Arzneimitteln in Deutschland.

The Federal Joint Committee (FJC; Gemeinsamer Bundesausschuss, G-BA) defines the health-care elements that are to be reimbursed by sickness funds. To define a directive, the FJC can commission benefit assessments, which provide an overview of the scientific evidence regarding the efficacy and benefits of an intervention. This paper describes the operational implementation of the legal requirements with regard to the benefit assessments of medicines. Such benefit assessments are sometimes referred to as "isolated benefit assessments," to distinguish them from benefit assessments as part of a full economic evaluation. The FJC has the freedom to commission these assessments from any agency; however, to date the majority have commissioned the Institute for Quality and Efficiency in Health Care (IQWiG). Nevertheless, the content of this paper applies integrally to any institute commissioned for such assessments. In this report, "the institute"' is used when the text refers to any of these institutes. The legal framework for benefit assessments is laid out in the German Social Code Book version V (http://www. sozialgesetzbuch.de), Sects. 35b ( section sign 1), 139a ( section sign 4-6) and Sect. 139b ( section sign 3). It is specified that: The institute must guarantee high transparency. The institute must provide appropriate participation of relevant parties for the commission-related development of assessments, and opportunity for comment on all important segments of the assessment procedure. The institute has to report on the progress and results of the work at regular intervals. The institute is held to giving the commission to external experts. Based on the legal framework, the institute must guarantee a high procedural transparency. Transparency of the whole process should be achieved, which is evidenced by clear reporting of procedures and criteria in all phases undertaken in the benefit assessment. The most important means of enhancing transparency are: 1. To implement a scoping process to support the development of the research question. 2. To separate the work of the external experts performing the evidence assessment from that of the institute formulating recommendations. Therefore, the preliminary report as produced by external experts needs to be public, and published separately from any subsequent amendments or (draft-)reports made by the institute, which includes the institute's recommendations. 3. To implement open peer review by publishing both the comments of the reviewers and their names. Based on the legal framework, the institute must provide for adequate participation of relevant parties. These include organisations representing the interests of patients; experts of medical, pharmaceutical and health economic science and practice; the professional organisations of pharmacists and pharmaceutical companies; and experts on alternative therapies. Patients and health care professionals bring in new insights with respect to research priorities, treatment and outcomes. The relevant parties should be identified and contacted whenever the global scope of the assessment has been drafted. Subsequently, the relevant parties should be involved in defining the research question, developing the protocol and commenting on the preliminary report. To implement the involvement of relevant parties in defining the research question a scoping process is suggested. For the other phases, written comments followed by an oral discussion should be used. Finally, the relevant parties should have the right to appeal the final decision on judicial grounds. None of these steps mean that the institute would lose any part of its scientific independence. From the relevant sections of the legal framework with respect to the assessment methods, it can be concluded that: 1. The institute must ensure that the assessment is made in accordance with internationally recognised standards of evidence-based medicine (EBM). 2. The assessment is conducted in comparison with other medicines and treatment forms under consideration of the additional therapeutic benefit for the patients. 3. The minimum criteria for assessing patient benefit are improvements in the state of health, shortening the duration of illness, extension of the duration of life, reduction of side effects and improvements in quality of life. EBM refers to the application of the best available evidence to answer a research question, which can inform questions about the care of patients. The optimal design, even for effectiveness questions, is not always the randomised, controlled trial (RCT) but depends on the research question and the outcomes of interest. To increase transparency for each question, the levels of evidence examined should be made explicit. There is no empirical evidence to support the use of cutoff points with respect to the number of studies before making recommendations. To get the best available evidence for the research question(s), all relevant evidence should be considered for each question, and the best available evidence should be used to answer the question. Separate levels of evidence may have to be used for each outcome. There are many ways in which bias can be introduced in systematic reviews. Some types of bias can be prevented, other types can only be reported and, for some, the influence of the bias can be investigated. Reviews must show that potential sources of bias have been dealt with adequately. Methods used by other agencies that perform benefit assessments are useful to interpret the term 'international standards' to which the institute must comply. The National Institute for Health and Clinical Excellence (NICE) is a good example in this respect. NICE shows that it is possible to have transparent procedures for benefit assessments but that this requires detailed documentation. NICE has implemented an open procedure with respect to the comments of reviewers, which makes the procedure transparent. Although the Institute for Quality and Efficiency in Health Care (IQWiG) in Germany invites comments on their protocol and preliminary report by posting them on their website, and comments are made public, the individual comments are not evaluated openly, and therefore it remains uncertain whether or not they lead to changes in the reports. The participation of relevant parties in the assessment process as implemented by NICE guarantees a process that is transparent to all relevant parties. Transparency of the whole process is assured by clear reporting of procedures and criteria in all phases undertaken in the benefit assessment. In a scoping process, a draft scope is commented on first in writing and subsequently in the form of a scoping workshop. In this way, all relevant aspects can be heard and included in the final scope. The protocol is then developed, followed by evidence assessment. The methods used should be completely reported to show readers that the assessment has been performed with scientific rigour and that bias has been prevented where possible. All relevant parties should have the opportunity to comment on the draft protocol and the draft preliminary report. Each comment should be evaluated as to whether or not it will lead to changes, and both the comments and the evaluation should be made public to ensure transparency of this process. The same procedure should be used for the peer-review phase. Based on the final report of the evidence assessment, the institute forms recommendations and the FJC appraises the evidence. During the writing of the final report, a separation between the evidence assessment and the evidence appraisal phase should be implemented. Ideally, this separation should be legally enforced to prevent any confusion about conflict of interests. Such a process guarantees a feasible combination of the legal requirements for transparency and involvement of relevant parties with international standards of EBM to ensure that the benefit assessments of medicines in Germany are performed according to the highest standards.

The application of quantitative methods for identifying and exploring the presence of bias in systematic reviews: PDE-5 inhibitors for erectile dysfunction.

A systematic review of PDE-5 inhibitors for erectile dysfunction was performed to evaluate the utility of quantitative methods for identifying and exploring the influence of bias and study quality on pooled outcomes from meta-analyses. We included 123 randomized controlled trials (RCTs). Methodological quality was poorly reported. All three drugs appeared highly effective. Indirect adjusted analyses showed no differences between the three drugs. Funnel plots and statistical tests showed no evidence of small-study effects for sildenafil whereas there was evidence of such bias for tadalafil and vardenafil. Adjustment for missing studies using trim and fill techniques did not alter the pooled estimates substantially. The exclusion of previous sildenafil nonresponders was associated with larger treatment effects for tadalafil. This investigation was hampered by poor reporting of methodological quality, a low number of studies, heterogeneity and large effect sizes. Despite such limitations, a comprehensive assessment of biases should be a routine in systematic reviews.

Effect on the process of care of an active strategy to implement clinical guidelines on physiotherapy for low back pain: a cluster randomised controlled trial.

OBJECTIVES: To evaluate the effect on the process of care of an active strategy to implement clinical guidelines on physiotherapy for low back pain. DESIGN: A cluster randomised controlled trial comparing an active strategy with standard dissemination. SETTING: Primary care physiotherapy practices. PARTICIPANTS: 113 physiotherapists were randomly allocated to receive the guidelines by mail (control group) or to receive an additional active strategy (intervention group) which consisted of a multifaceted programme including education, discussion, role playing, feedback, and reminders. MAIN OUTCOME MEASURES: Adherence to the guidelines was measured by means of individual patients' forms recording the treatment completed by the physiotherapist. The forms were assessed using an algorithm based on the number of treatment sessions, treatment goals, interventions, and patient education. RESULTS: Physiotherapists in the intervention group more often correctly limited the number of treatment sessions for patients with a normal course of back pain (OR 2.39; 95% CI 1.12 to 5.12), more often set functional treatment goals (OR 1.99; 95% CI 1.06 to 3.72), more often used mainly active interventions (OR 2.79; 95% CI 1.19 to 6.55), and more often gave adequate patient education (OR 3.59; 95% CI 1.35 to 9.55). They also adhered more to all four criteria (OR 2.05; 95% CI 1.15 to 3.65). CONCLUSIONS: The active strategy moderately improved adherence to the guidelines. Active strategies are recommended to implement the clinical guidelines on physiotherapy for low back pain.