Which clinical research questions are the most important? Development and preliminary validation of the Australia & New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network Research Question Importance Tool (ANZMUSC-RQIT).

BACKGROUND AND AIMS: High quality clinical research that addresses important questions requires significant resources. In resource-constrained environments, projects will therefore need to be prioritized. The Australia and New Zealand Musculoskeletal (ANZMUSC) Clinical Trials Network aimed to develop a stakeholder-based, transparent, easily implementable tool that provides a score for the 'importance' of a research question which could be used to rank research projects in order of importance. METHODS: Using a mixed-methods, multi-stage approach that included a Delphi survey, consensus workshop, inter-rater reliability testing, validity testing and calibration using a discrete-choice methodology, the Research Question Importance Tool (ANZMUSC-RQIT) was developed. The tool incorporated broad stakeholder opinion, including consumers, at each stage and is designed for scoring by committee consensus. RESULTS: The ANZMUSC-RQIT tool consists of 5 dimensions (compared to 6 dimensions for an earlier version of RQIT): (1) extent of stakeholder consensus, (2) social burden of health condition, (3) patient burden of health condition, (4) anticipated effectiveness of proposed intervention, and (5) extent to which health equity is addressed by the research. Each dimension is assessed by defining ordered levels of a relevant attribute and by assigning a score to each level. The scores for the dimensions are then summed to obtain an overall ANZMUSC-RQIT score, which represents the importance of the research question. The result is a score on an interval scale with an arbitrary unit, ranging from 0 (minimal importance) to 1000. The ANZMUSC-RQIT dimensions can be reliably ordered by committee consensus (ICC 0.73-0.93) and the overall score is positively associated with citation count (standardised regression coefficient 0.33, p<0.001) and journal impact factor group (OR 6.78, 95% CI 3.17 to 14.50 for 3rd tertile compared to 1st tertile of ANZMUSC-RQIT scores) for 200 published musculoskeletal clinical trials. CONCLUSION: We propose that the ANZMUSC-RQIT is a useful tool for prioritising the importance of a research question.

Evaluation of the Incremental Value of a Coronary Artery Calcium Score Beyond Traditional Cardiovascular Risk Assessment: A Systematic Review and Meta-analysis.

Importance: Coronary artery calcium scores (CACS) are used to help assess patients' cardiovascular status and risk. However, their best use in risk assessment beyond traditional cardiovascular factors in primary prevention is uncertain. Objective: To find, assess, and synthesize all cohort studies that assessed the incremental gain from the addition of a CACS to a standard cardiovascular disease (CVD) risk calculator (or CVD risk factors for a standard calculator), that is, comparing CVD risk score plus CACS with CVD risk score alone. Evidence Review: Eligible studies needed to be cohort studies in primary prevention populations that used 1 of the CVD risk calculators recommended by national guidelines (Framingham Risk Score, QRISK, pooled cohort equation, NZ PREDICT, NORRISK, or SCORE) and assessed and reported incremental discrimination with CACS for estimating the risk of a future cardiovascular event. Findings: From 2772 records screened, 6 eligible cohort studies were identified (with 1043 CVD events in 17 961 unique participants) from the US (n = 3), the Netherlands (n = 1), Germany (n = 1), and South Korea (n = 1). Studies varied in size from 470 to 5185 participants (range of mean [SD] ages, 50 [10] to 75.1 [7.3] years; 38.4%-59.4% were women). The C statistic for the CVD risk models without CACS ranged from 0.693 (95% CI, 0.661-0.726) to 0.80. The pooled gain in C statistic from adding CACS was 0.036 (95% CI, 0.020-0.052). Among participants classified as being at low risk by the risk score and reclassified as at intermediate or high risk by CACS, 85.5% (65 of 76) to 96.4% (349 of 362) did not have a CVD event during follow-up (range, 5.1-10.0 years). Among participants classified as being at high risk by the risk score and reclassified as being at low risk by CACS, 91.4% (202 of 221) to 99.2% (502 of 506) did not have a CVD event during follow-up. Conclusions and Relevance: This systematic review and meta-analysis found that the CACS appears to add some further discrimination to the traditional CVD risk assessment equations used in these studies, which appears to be relatively consistent across studies. However, the modest gain may often be outweighed by costs, rates of incidental findings, and radiation risks. Although the CACS may have a role for refining risk assessment in selected patients, which patients would benefit remains unclear. At present, no evidence suggests that adding CACS to traditional risk scores provides clinical benefit.

Kidney trajectory charts to assist general practitioners in the assessment of patients with reduced kidney function: a randomised vignette study.

OBJECTIVE: To investigate the decisional impact of an age-based chart of kidney function decline to support general practitioners (GPs) to appropriately interpret estimated glomerular filtration rate (eGFR) and identify patients with a clinically relevant kidney problem. DESIGN AND SETTING: Randomised vignette study PARTICIPANTS: 372 Australian GPs from August 2018 to November 2018. INTERVENTION: GPs were given two patient case scenarios: (1) an older woman with reduced but stable renal function and (2) a younger Aboriginal man with declining kidney function still in the normal range. One group was given an age-based chart of kidney function to assist their assessment of the patient (initial chart group); the second group was asked to assess the patients without the chart, and then again using the chart (delayed chart group). MAIN OUTCOME MEASURES: GPs' assessment of the likelihood-on a Likert scale-that the patients had chronic kidney disease (CKD) according to the usual definition or a clinical problem with their kidneys. RESULTS: Prior to viewing the age-based chart GPs were evenly distributed as to whether they thought case 1-the older woman-had CKD or a clinically relevant kidney problem. GPs who had initial access to the chart were less likely to think that the older woman had CKD, and less likely to think she had a clinically relevant problem with her kidneys than GPs who had not viewed the chart. After subsequently viewing the chart, 14% of GPs in the delayed chart group changed their opinion, to indicate she was unlikely to have a clinically relevant problem with her kidneys.Prior to viewing the chart, the majority of GPs (66%) thought case 2-the younger man-did not have CKD, and were evenly distributed as to whether they thought he had a clinically relevant kidney problem. In contrast, GPs who had initial access to the chart were more likely to think he had CKD and the majority (72%) thought he had a clinically relevant kidney problem. After subsequently viewing the chart, 37% of GPs in the delayed chart group changed their opinion to indicate he likely had a clinically relevant problem with his kidneys. CONCLUSIONS: Use of the chart changed GPs interpretation of eGFR, with increased recognition of the younger male patient's clinically relevant kidney problem, and increased numbers classifying the older female patient's kidney function as normal for her age. This study has shown the potential of an age-based kidney function chart to reduce both overdiagnosis and underdiagnosis.

Effectiveness of the application of an electronic medication management support system in patients with polypharmacy in general practice: a study protocol of cluster-randomised controlled trial (AdAM).

INTRODUCTION: Clinically complex patients often require multiple medications. Polypharmacy is associated with inappropriate prescriptions, which may lead to negative outcomes. Few effective tools are available to help physicians optimise patient medication. This study assesses whether an electronic medication management support system (eMMa) reduces hospitalisation and mortality and improves prescription quality/safety in patients with polypharmacy. METHODS AND ANALYSIS: Planned design: pragmatic, parallel cluster-randomised controlled trial; general practices as randomisation unit; patients as analysis unit. As practice recruitment was poor, we included additional data to our primary endpoint analysis for practices and quarters from October 2017 to March 2021. Since randomisation was performed in waves, final study design corresponds to a stepped-wedge design with open cohort and step-length of one quarter. SCOPE: general practices, Westphalia-Lippe (Germany), caring for BARMER health fund-covered patients. POPULATION: patients (≥18 years) with polypharmacy (≥5 prescriptions). SAMPLE SIZE: initially, 32 patients from each of 539 practices were required for each study arm (17 200 patients/arm), but only 688 practices were randomised after 2 years of recruitment. Design change ensures that 80% power is nonetheless achieved. INTERVENTION: complex intervention eMMa. FOLLOW-UP: at least five quarters/cluster (practice). recruitment: practices recruited/randomised at different times; after follow-up, control group practices may access eMMa. OUTCOMES: primary endpoint is all-cause mortality and hospitalisation; secondary endpoints are number of potentially inappropriate medications, cause-specific hospitalisation preceded by high-risk prescribing and medication underuse. STATISTICAL ANALYSIS: primary and secondary outcomes are measured quarterly at patient level. A generalised linear mixed-effect model and repeated patient measurements are used to consider patient clusters within practices. Time and intervention group are considered fixed factors; variation between practices and patients is fitted as random effects. Intention-to-treat principle is used to analyse primary and key secondary endpoints. ETHICS AND DISSEMINATION: Trial approved by Ethics Commission of North-Rhine Medical Association. Results will be disseminated through workshops, peer-reviewed publications, local and international conferences. TRIAL REGISTRATION: NCT03430336. ClinicalTrials.gov (https://clinicaltrials.gov/ct2/show/NCT03430336).

Systematic review automation tools improve efficiency but lack of knowledge impedes their adoption: a survey.

OBJECTIVE: We investigated systematic review automation tool use by systematic reviewers, health technology assessors and clinical guideline developerst. STUDY DESIGN AND SETTING: An online, 16-question survey was distributed across several evidence synthesis, health technology assessment and guideline development organizations. We asked the respondents what tools they use and abandon, how often and when do they use the tools, their perceived time savings and accuracy, and desired new tools. Descriptive statistics were used to report the results. RESULTS: A total of 253 respondents completed the survey; 89% have used systematic review automation tools - most frequently whilst screening (79%). Respondents' "top 3" tools included: Covidence (45%), RevMan (35%), Rayyan and GRADEPro (both 22%); most commonly abandoned were Rayyan (19%), Covidence (15%), DistillerSR (14%) and RevMan (13%). Tools saved time (80%) and increased accuracy (54%). Respondents taught themselves to how to use the tools (72%); lack of knowledge was the most frequent barrier to tool adoption (51%). New tool development was suggested for the searching and data extraction stages. CONCLUSION: Automation tools will likely have an increasingly important role in high-quality and timely reviews. Further work is required in training and dissemination of automation tools and ensuring they meet the desirable features of those conducting systematic reviews.

Prioritising models of healthcare service delivery for a more sustainable health system: a Delphi study of Australian health policy, clinical practice and management, academic and consumer stakeholders.

Objectives Healthcare expenditure is growing at an unsustainable rate in developed countries. A recent scoping review identified several alternative healthcare delivery models with the potential to improve health system sustainability. Our objective was to obtain input and consensus from an expert Delphi panel about which alternative models they considered most promising for increasing value in healthcare delivery in Australia and to contribute to shaping a research agenda in the field. Methods The panel first reviewed a list of 84 models obtained through the preceding scoping review and contributed additional ideas in an open round. In a subsequent scoring round, the panel rated the priority of each model in terms of its potential to improve health care sustainability in Australia. Consensus was assumed when ≥50% of the panel rated a model as (very) high priority (consensus on high priority) or as not a priority or low priority (consensus on low priority). Results Eighty-two of 149 invited participants (55%) representing all Australian states/territories and wide expertise completed round one; 71 completed round two. Consensus on high priority was achieved for 59 alternative models; 14 were rated as (very) high priority by ≥70% of the panel. Top priorities included improving medical service provision in aged care facilities, providing single-point-access multidisciplinary care for people with chronic conditions and providing tailored early discharge and hospital at home instead of in-patient care. No consensus was reached on 47 models, but no model was deemed low priority. Conclusions Input from an expert stakeholder panel identified healthcare delivery models not previously synthesised in systematic reviews that are a priority to investigate. Strong consensus exists among stakeholders regarding which models require the most urgent attention in terms of (cost-)effectiveness research. These findings contribute to shaping a research agenda on healthcare delivery models and where stakeholder engagement in Australia is likely to be high. What is known about the topic? Healthcare expenditure is growing at an unsustainable rate in high-income countries worldwide. A recent scoping review of systematic reviews identified a substantial body of evidence about the effects of a wide range of models of healthcare service delivery that can inform health system improvements. Given the large number of systematic reviews available on numerous models of care, a method for gaining consensus on the models of highest priority for implementation (where evidence demonstrates this will lead to beneficial effects and resource savings) or for further research (where evidence about effects is uncertain) in the Australian context is warranted. What does this paper add? This paper describes a method for reaching consensus on high-priority alternative models of service delivery in Australia. Stakeholders with leadership roles in health policy and government organisations, hospital and primary care networks, academic institutions and consumer advocacy organisations were asked to identify and rate alternative models based on their knowledge of the healthcare system. We reached consensus among ≥70% of stakeholders that improving medical care in residential aged care facilities, providing single-point-access multidisciplinary care for patients with a range of chronic conditions and providing early discharge and hospital at home instead of in-patient stay for people with a range of conditions are of highest priority for further investigation. What are the implications for practitioners? Decision makers seeking to optimise the efficiency and sustainability of healthcare service delivery in Australia could consider the alternative models rated as high priority by the expert stakeholder panel in this Delphi study. These models reflect the most promising alternatives for increasing value in the delivery of health care in Australia based on stakeholders' knowledge of the health system. Although they indicate areas where stakeholder engagement is likely to be high, further research is needed to demonstrate the effectiveness and cost-effectiveness of some of these models.

Corticosteroids as standalone or add-on treatment for sore throat.

BACKGROUND: Sore throat is a common condition associated with a high rate of antibiotic prescriptions, despite limited evidence for the effectiveness of antibiotics. Corticosteroids may improve symptoms of sore throat by reducing inflammation of the upper respiratory tract. This review is an update to our review published in 2012. OBJECTIVES: To assess the clinical benefit and safety of corticosteroids in reducing the symptoms of sore throat in adults and children. SEARCH METHODS: We searched CENTRAL (Issue 4, 2019), MEDLINE (1966 to 14 May 2019), Embase (1974 to 14 May 2019), the Database of Abstracts of Reviews of Effects (DARE, 2002 to 2015), and the NHS Economic Evaluation Database (inception to 2015). We also searched the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP) and ClinicalTrials.gov. SELECTION CRITERIA: We included randomised controlled trials (RCTs) that compared steroids to either placebo or standard care in adults and children (aged over three years) with sore throat. We excluded studies of hospitalised participants, those with infectious mononucleosis (glandular fever), sore throat following tonsillectomy or intubation, or peritonsillar abscess. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by Cochrane. MAIN RESULTS: We included one new RCT in this update, for a total of nine trials involving 1319 participants (369 children and 950 adults). In eight trials, participants in both corticosteroid and placebo groups received antibiotics; one trial offered delayed prescription of antibiotics based on clinical assessment. Only two trials reported funding sources (government and a university foundation). In addition to any effect of antibiotics and analgesia, corticosteroids increased the likelihood of complete resolution of pain at 24 hours by 2.40 times (risk ratio (RR) 2.4, 95% confidence interval (CI) 1.29 to 4.47; P = 0.006; I² = 67%; high-certainty evidence) and at 48 hours by 1.5 times (RR 1.50, 95% CI 1.27 to 1.76; P < 0.001; I² = 0%; high-certainty evidence). Five people need to be treated to prevent one person continuing to experience pain at 24 hours. Corticosteroids also reduced the mean time to onset of pain relief and the mean time to complete resolution of pain by 6 and 11.6 hours, respectively, although significant heterogeneity was present (moderate-certainty evidence). At 24 hours, pain (assessed by visual analogue scales) was reduced by an additional 10.6% by corticosteroids (moderate-certainty evidence). No differences were reported in recurrence/relapse rates, days missed from work or school, or adverse events for participants taking corticosteroids compared to placebo. However, the reporting of adverse events was poor, and only two trials included children or reported days missed from work or school. The included studies were assessed as moderate quality evidence, but the small number of included studies has the potential to increase the uncertainty, particularly in terms of applying these results to children. AUTHORS' CONCLUSIONS: Oral or intramuscular corticosteroids, in addition to antibiotics, moderately increased the likelihood of both resolution and improvement of pain in participants with sore throat. Given the limited benefit, further research into the harms and benefits of short courses of steroids is needed to permit informed decision-making.

Generating comparative evidence on new drugs and devices after approval.

Certain limitations of evidence available on drugs and devices at the time of market approval often persist in the post-marketing period. Often, post-marketing research landscape is fragmented. When regulatory agencies require pharmaceutical and device manufacturers to conduct studies in the post-marketing period, these studies might remain incomplete many years after approval. Even when completed, many post-marketing studies lack meaningful active comparators, have observational designs, and might not collect patient-relevant outcomes. Regulators, in collaboration with the industry and patients, ought to ensure that the key questions unanswered at the time of drug and device approval are resolved in a timely fashion during the post-marketing phase. We propose a set of seven key guiding principles that we believe will provide the necessary incentives for pharmaceutical and device manufacturers to generate comparative data in the post-marketing period. First, regulators (for drugs and devices), notified bodies (for devices in Europe), health technology assessment organisations, and payers should develop customised evidence generation plans, ensuring that future post-approval studies address any limitations of the data available at the time of market entry impacting the benefit-risk profiles of drugs and devices. Second, post-marketing studies should be designed hierarchically: priority should be given to efforts aimed at evaluating a product's net clinical benefit in randomised trials compared with current known effective therapy, whenever possible, to address common decisional dilemmas. Third, post-marketing studies should incorporate active comparators as appropriate. Fourth, use of non-randomised studies for the evaluation of clinical benefit in the post-marketing period should be limited to instances when the magnitude of effect is deemed to be large or when it is possible to reasonably infer the comparative benefits or risks in settings, in which doing a randomised trial is not feasible. Fifth, efficiency of randomised trials should be improved by streamlining patient recruitment and data collection through innovative design elements. Sixth, governments should directly support and facilitate the production of comparative post-marketing data by investing in the development of collaborative research networks and data systems that reduce the complexity, cost, and waste of rigorous post-marketing research efforts. Last, financial incentives and penalties should be developed or more actively reinforced.

GRADE guidelines: 21 part 1. Study design, risk of bias, and indirectness in rating the certainty across a body of evidence for test accuracy.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can assess the results and the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA). STUDY DESIGN AND SETTING: We present an overview of the GRADE approach and guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. Part 1 of the two parts in this 21st guidance article about how to apply GRADE focuses on understanding study design issues in test accuracy, provide an overview of the domains, and describe risk of bias and indirectness specifically. RESULTS: Supplemented by practical examples, we describe how raters of the evidence using GRADE can evaluate study designs focusing on tests and how they apply the GRADE domains risk of bias and indirectness to a body of evidence of TA studies. CONCLUSION: Rating the certainty of a body of evidence using GRADE in Cochrane and other reviews and World Health Organization and other guidelines dealing with in TA studies helped refining our approach. The resulting guidance will help applying GRADE successfully for questions and recommendations focusing on tests.

GRADE guidelines: 21 part 2. Test accuracy: inconsistency, imprecision, publication bias, and other domains for rating the certainty of evidence and presenting it in evidence profiles and summary of findings tables.

OBJECTIVES: This article provides updated GRADE guidance about how authors of systematic reviews and health technology assessments and guideline developers can rate the certainty of evidence (also known as quality of the evidence or confidence in the estimates) of a body of evidence addressing test accuracy (TA) on the domains imprecision, inconsistency, publication bias, and other domains. It also provides guidance for how to present synthesized information in evidence profiles and summary of findings tables. STUDY DESIGN AND SETTING: We present guidance for rating certainty in TA in clinical and public health and review the presentation of results of a body of evidence regarding tests. RESULTS: Supplemented by practical examples, we describe how raters of the evidence can apply the GRADE domains inconsistency, imprecision, and publication bias to a body of evidence of TA studies. CONCLUSION: Using GRADE in Cochrane and other reviews as well as World Health Organization and other guidelines helped refining the GRADE approach for rating the certainty of a body of evidence from TA studies. Although several of the GRADE domains (e.g., imprecision and magnitude of the association) require further methodological research to help operationalize them, judgments need to be made on the basis of what is known so far.

Acute Increases in Serum Creatinine After Starting Angiotensin-Converting Enzyme Inhibitor-Based Therapy and Effects of its Continuation on Major Clinical Outcomes in Type 2 Diabetes Mellitus.

Discontinuation of angiotensin-converting enzyme (ACE) inhibitor is recommended if patients experience ≥30% acute increase in serum creatinine after starting this therapy. However, the long-term effects of its continuation or discontinuation on major clinical outcomes after increases in serum creatinine are unclear. In the ADVANCE trial (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation), 11 140 diabetes mellitus patients were randomly assigned to perindopril-indapamide or placebo after a 6-week active run-in period. The current study included 11 066 participants with 2 serum creatinine measurements recorded before and during the active run-in period (3 weeks apart). Acute increase in creatinine was determined using these 2 measurements and classified into 4 groups: increases in serum creatinine of <10%, 10% to 19%, 20% to 29%, and ≥30%. The primary study outcome was the composite of major macrovascular events, new or worsening nephropathy, and all-cause mortality. An acute increase in serum creatinine was associated with an elevated risk of the primary outcome ( P for trend <0.001). The hazard ratios were 1.11 (95% CI, 0.97-1.28) for those with an increase of 10% to 19%, 1.34 (1.07-1.66) for 20% to 29%, and 1.44 (1.15-1.81) for ≥30%, compared with <10%. However, there was no evidence of heterogeneity in the benefit of randomized treatment effects on the outcome across subgroups defined by acute serum creatinine increase ( P for heterogeneity=0.94). Acute increases in serum creatinine after starting perindopril-indapamide were associated with greater risks of subsequent major clinical outcomes. However, the continuation of angiotensin-converting enzyme inhibitor-based therapy reduced the long-term risk of major clinical outcomes, irrespective of acute increase in creatinine. Clinical Trial Registration- URL: http://www.clinicaltrials.gov . Unique identifier: NCT00145925.

Sustaining knowledge translation interventions for chronic disease management in older adults: protocol for a systematic review and network meta-analysis.

BACKGROUND: Failure to sustain knowledge translation (KT) interventions impacts patients and health systems, diminishing confidence in future implementation. Sustaining KT interventions used to implement chronic disease management (CDM) interventions is of critical importance given the proportion of older adults with chronic diseases and their need for ongoing care. Our objectives are to (1) complete a systematic review and network meta-analysis of the effectiveness and cost-effectiveness of sustainability of KT interventions that target CDM for end-users including older patients, clinicians, public health officials, health services managers and policy-makers on health care outcomes beyond 1 year after implementation or the termination of initial project funding and (2) use the results of this review to complete an economic analysis of the interventions identified to be effective. METHODS: For objective 1, comprehensive searches of relevant electronic databases (e.g. MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials), websites of health care provider organisations and funding agencies will be conducted. We will include randomised controlled trials (RCTs) examining the impact of a KT intervention targeting CDM in adults aged 65 years and older. To examine cost, economic studies (e.g. cost, cost-effectiveness analyses) will be included. Our primary outcome will be the sustainability of the delivery of the KT intervention beyond 1 year after implementation or termination of study funding. Secondary outcomes will include behaviour changes at the level of the patient (e.g. symptom management) and clinician (e.g. physician test ordering) and health system (e.g. cost, hospital admissions). Article screening, data abstraction and risk of bias assessment will be completed independently by two reviewers. Using established methods, if the assumption of transitivity is valid and the evidence forms a connected network, Bayesian random-effects pairwise and network meta-analysis will be conducted. For objective 2, we will build a decision analytic model comparing effective interventions to estimate an incremental cost-effectiveness ratio. DISCUSSION: Our results will inform knowledge users (e.g. patients, clinicians, policy-makers) regarding the sustainability of KT interventions for CDM. Dissemination plan of our results will be tailored to end-users and include passive (e.g. publications, website posting) and interactive (e.g. knowledge exchange events with stakeholders) strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084810.

Should heart age calculators be used alongside absolute cardiovascular disease risk assessment?

BACKGROUND: National estimates of 'heart age' by government health organisations in the US, UK and China show most people have an older heart age than current age. While most heart age calculators are promoted as a communication tool for lifestyle change, they may also be used to justify medication when clinical guidelines advocate their use alongside absolute risk assessment. However, only those at high absolute risk of a heart attack or stroke are likely to benefit from medication, and it is not always clear how heart age relates to absolute risk. This article aims to: 1) explain how heart age calculation methods relate to absolute risk guidelines; 2) summarise research investigating whether heart age improves risk communication; and 3) discuss implications for the use of medication and shared decision making in clinical practice. MAIN BODY: There is a large and growing number of heart age models and online calculators, but the clinical meaning of an older heart age result is highly variable. An older heart age result may indicate low, moderate or high absolute risk of a heart attack or stroke in the next 5-10 years, and the same individual may receive a younger or older heart age result depending on which calculator is used. Heart age may help doctors convey the need to change lifestyle, but it cannot help patients make an informed choice about medication to reduce CVD risk. CONCLUSION: Interactive heart age tools may be helpful as a communication tool to initiate lifestyle change to reduce risk factors. However, absolute risk should be used instead of heart age to enable informed decision making about medication, to avoid unnecessary treatment of low risk people. Evidence-based decision aids that improve patient understanding of absolute risk should be considered as alternatives to heart age calculators for lifestyle and medication decisions.

B-type natriuretic peptide-guided treatment for heart failure.

BACKGROUND: Heart failure is a condition in which the heart does not pump enough blood to meet all the needs of the body. Symptoms of heart failure include breathlessness, fatigue and fluid retention. Outcomes for patients with heart failure are highly variable; however on average, these patients have a poor prognosis. Prognosis can be improved with early diagnosis and appropriate use of medical treatment, use of devices and transplantation. Patients with heart failure are high users of healthcare resources, not only due to drug and device treatments, but due to high costs of hospitalisation care. B-type natriuretic peptide levels are already used as biomarkers for diagnosis and prognosis of heart failure, but could offer to clinicians a possible tool to guide drug treatment. This could optimise drug management in heart failure patients whilst allaying concerns over potential side effects due to drug intolerance. OBJECTIVES: To assess whether treatment guided by serial BNP or NT-proBNP (collectively referred to as NP) monitoring improves outcomes compared with treatment guided by clinical assessment alone. SEARCH METHODS: Searches were conducted up to 15 March 2016 in the Cochrane Central Register of Controlled Trials (CENTRAL) in the Cochrane Library; MEDLINE (OVID), Embase (OVID), the Database of Abstracts of Reviews of Effects (DARE) and the NHS Economic Evaluation Database in the Cochrane Library. Searches were also conducted in the Science Citation Index Expanded, the Conference Proceedings Citation Index on Web of Science (Thomson Reuters), World Health Organization International Clinical Trials Registry and ClinicalTrials.gov. We applied no date or language restrictions. SELECTION CRITERIA: We included randomised controlled trials of NP-guided treatment of heart failure versus treatment guided by clinical assessment alone with no restriction on follow-up. Adults treated for heart failure, in both in-hospital and out-of-hospital settings, and trials reporting a clinical outcome were included. DATA COLLECTION AND ANALYSIS: Two review authors independently selected studies for inclusion, extracted data and evaluated risk of bias. Risk ratios (RR) were calculated for dichotomous data, and pooled mean differences (MD) (with 95% confidence intervals (CI)) were calculated for continuous data. We contacted trial authors to obtain missing data. Using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach, we assessed the quality of the evidence and GRADE profiler (GRADEPRO) was used to import data from Review Manager to create a 'Summary of findings' table. MAIN RESULTS: We included 18 randomised controlled trials with 3660 participants (range of mean age: 57 to 80 years) comparing NP-guided treatment with clinical assessment alone. The evidence for all-cause mortality using NP-guided treatment showed uncertainty (RR 0.87, 95% CI 0.76 to 1.01; patients = 3169; studies = 15; low quality of the evidence), and for heart failure mortality (RR 0.84, 95% CI 0.54 to 1.30; patients = 853; studies = 6; low quality of evidence).The evidence suggested heart failure admission was reduced by NP-guided treatment (38% versus 26%, RR 0.70, 95% CI 0.61 to 0.80; patients = 1928; studies = 10; low quality of evidence), but the evidence showed uncertainty for all-cause admission (57% versus 53%, RR 0.93, 95% CI 0.84 to 1.03; patients = 1142; studies = 6; low quality of evidence).Six studies reported on adverse events, however the results could not be pooled (patients = 1144; low quality of evidence). Only four studies provided cost of treatment results, three of these studies reported a lower cost for NP-guided treatment, whilst one reported a higher cost (results were not pooled; patients = 931, low quality of evidence). The evidence showed uncertainty for quality of life data (MD -0.03, 95% CI -1.18 to 1.13; patients = 1812; studies = 8; very low quality of evidence).We completed a 'Risk of bias' assessment for all studies. The impact of risk of bias from lack of blinding of outcome assessment and high attrition levels was examined by restricting analyses to only low 'Risk of bias' studies. AUTHORS' CONCLUSIONS: In patients with heart failure low-quality evidence showed a reduction in heart failure admission with NP-guided treatment while low-quality evidence showed uncertainty in the effect of NP-guided treatment for all-cause mortality, heart failure mortality, and all-cause admission. Uncertainty in the effect was further shown by very low-quality evidence for patient's quality of life. The evidence for adverse events and cost of treatment was low quality and we were unable to pool results.

Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: a systematic review with statistical and cost-effectiveness modelling.

BACKGROUND: Various lipid measurements in monitoring/screening programmes can be used, alone or in cardiovascular risk scores, to guide treatment for prevention of cardiovascular disease (CVD). Because some changes in lipids are due to variability rather than true change, the value of lipid-monitoring strategies needs evaluation. OBJECTIVE: To determine clinical value and cost-effectiveness of different monitoring intervals and different lipid measures for primary and secondary prevention of CVD. DATA SOURCES: We searched databases and clinical trials registers from 2007 (including the Cochrane Central Register of Controlled Trials, MEDLINE, EMBASE, the Clinical Trials Register, the Current Controlled Trials register, and the Cumulative Index to Nursing and Allied Health Literature) to update and extend previous systematic reviews. Patient-level data from the Clinical Practice Research Datalink and St Luke's Hospital, Japan, were used in statistical modelling. Utilities and health-care costs were drawn from the literature. METHODS: In two meta-analyses, we used prospective studies to examine associations of lipids with CVD and mortality, and randomised controlled trials to estimate lipid-lowering effects of atorvastatin doses. Patient-level data were used to estimate progression and variability of lipid measurements over time, and hence to model lipid-monitoring strategies. Results are expressed as rates of true-/false-positive and true-/false-negative tests for high lipid or high CVD risk. We estimated incremental costs per quality-adjusted life-year. RESULTS: A total of 115 publications reported strength of association between different lipid measures and CVD events in 138 data sets. The summary adjusted hazard ratio per standard deviation of total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio was 1.25 (95% confidence interval 1.15 to 1.35) for CVD in a primary prevention population but heterogeneity was high (I(2) = 98%); similar results were observed for non-HDL cholesterol, apolipoprotein B and other ratio measures. Associations were smaller for other single lipid measures. Across 10 trials, low-dose atorvastatin (10 and 20 mg) effects ranged from a TC reduction of 0.92 mmol/l to 2.07 mmol/l, and low-density lipoprotein reduction of between 0.88 mmol/l and 1.86 mmol/l. Effects of 40 mg and 80 mg were reported by one trial each. For primary prevention, over a 3-year period, we estimate annual monitoring would unnecessarily treat 9 per 1000 more men (28 vs. 19 per 1000) and 5 per 1000 more women (17 vs. 12 per 1000) than monitoring every 3 years. However, annual monitoring would also undertreat 9 per 1000 fewer men (7 vs. 16 per 1000) and 4 per 1000 fewer women (7 vs. 11 per 1000) than monitoring at 3-year intervals. For secondary prevention, over a 3-year period, annual monitoring would increase unnecessary treatment changes by 66 per 1000 men and 31 per 1000 women, and decrease undertreatment by 29 per 1000 men and 28 per 1000 men, compared with monitoring every 3 years. In cost-effectiveness, strategies with increased screening/monitoring dominate. Exploratory analyses found that any unknown harms of statins would need utility decrements as large as 0.08 (men) to 0.11 (women) per statin user to reverse this finding in primary prevention. LIMITATION: Heterogeneity in meta-analyses. CONCLUSIONS: While acknowledging known and potential unknown harms of statins, we find that more frequent monitoring strategies are cost-effective compared with others. Regular lipid monitoring in those with and without CVD is likely to be beneficial to patients and to the health service. Future research should include trials of the benefits and harms of atorvastatin 40 and 80 mg, large-scale surveillance of statin safety, and investigation of the effect of monitoring on medication adherence. STUDY REGISTRATION: This study is registered as PROSPERO CRD42013003727. FUNDING: The National Institute for Health Research Health Technology Assessment programme.