Areas Of Clinical Uncertainty Research Articles

Optimising the use of the prostate- specific antigen blood test in asymptomatic men for early prostate cancer detection in primary care: report from a UK clinical consensus.

Screening is not recommended for prostate cancer in the UK. Asymptomatic men aged ≥50 years can request a prostate-specific antigen (PSA) test following counselling on potential harms and benefits. There are areas of clinical uncertainty among GPs, resulting in the content and quality of counselling varying. To produce a consensus that can influence guidelines for UK primary care on the optimal use of the PSA test in asymptomatic men for early prostate cancer detection. Prostate Cancer UK facilitated a RAND/UCLA consensus. Statements covering five topics were developed with a subgroup of experts. A panel of 15 experts in prostate cancer scored (round one) statements on a scale of one (strongly disagree) to nine (strongly agree). Panellists met to discuss statements before rescoring (round two). A lived experience panel of seven men scored a subset of statements with outcomes fed into the main panel. Of the initial 94 statements reviewed by the expert panel, a final 48/85 (56%) achieved consensus. In the absence of screening, there was consensus on proactive approaches to initiate discussions about the PSA test with men who were at higher-than-average risk. Improvements in the prostate cancer diagnostic pathway may have reduced some of the harms associated with PSA testing; however, several areas of uncertainty remain in relation to screening, including optimal PSA thresholds for referral and intervals for retesting. There is consensus on proactive approaches to testing in higher-than-average risk groups. This should prompt a review of current guidelines.

Consensus Panel Recommendations for the Pharmacological Management of Pregnant Women with Depressive Disorders.

The initiative of a consensus on the topic of antidepressant and anxiolytic drug use in pregnancy is developing in an area of clinical uncertainty. Although many studies have been published in recent years, there is still a paucity of authoritative evidence-based indications useful for guiding the prescription of these drugs during pregnancy, and the data from the literature are complex and require expert judgment to draw clear conclusions. For the elaboration of the consensus, we have involved the scientific societies of the sector, namely, the Italian Society of Toxicology, the Italian Society of Neuropsychopharmacology, the Italian Society of Psychiatry, the Italian Society of Obstetrics and Gynecology, the Italian Society of Drug Addiction and the Italian Society of Addiction Pathology. An interdisciplinary team of experts from different medical specialties (toxicologists, pharmacologists, psychiatrists, gynecologists, neonatologists) was first established to identify the needs underlying the consensus. The team, in its definitive structure, includes all the representatives of the aforementioned scientific societies; the task of the team was the evaluation of the most accredited international literature as well as using the methodology of the "Nominal Group Technique" with the help of a systematic review of the literature and with various discussion meetings, to arrive at the drafting and final approval of the document. The following five areas of investigation were identified: (1) The importance of management of anxiety and depressive disorders in pregnancy, identifying the risks associated with untreated maternal depression in pregnancy. (2) The assessment of the overall risk of malformations with the antidepressant and anxiolytic drugs used in pregnancy. (3) The evaluation of neonatal adaptation disorders in the offspring of pregnant antidepressant/anxiolytic-treated women. (4) The long-term outcome of infants' cognitive development or behavior after in utero exposure to antidepressant/anxiolytic medicines. (5) The evaluation of pharmacological treatment of opioid-abusing pregnant women with depressive disorders. Considering the state of the art, it is therefore necessary in the first instance to frame the issue of pharmacological choices in pregnant women who need treatment with antidepressant and anxiolytic drugs on the basis of data currently available in the literature. Particular attention must be paid to the evaluation of the risk/benefit ratio, understood both in terms of therapeutic benefit with respect to the potential risks of the treatment on the pregnancy and on the fetal outcome, and of the comparative risk between the treatment and the absence of treatment; in the choice prescription, the specialist needs to be aware of both the potential risks of pharmacological treatment and the equally important risks of an untreated or undertreated disorder.

Personalizing cholesterol treatment recommendations for primary cardiovascular disease prevention

Statin therapy is the cornerstone of preventing atherosclerotic cardiovascular disease (ASCVD), primarily by reducing low density lipoprotein cholesterol (LDL-C) levels. Optimal statin therapy decisions rely on shared decision making and may be uncertain for a given patient. In areas of clinical uncertainty, personalized approaches based on real-world data may help inform treatment decisions. We sought to develop a personalized statin recommendation approach for primary ASCVD prevention based on historical real-world outcomes in similar patients. Our retrospective cohort included adults from a large Northern California electronic health record (EHR) aged 40–79 years with no prior cardiovascular disease or statin use. The cohort was split into training and test sets. Weighted-K-nearest-neighbor (wKNN) regression models were used to identify historical EHR patients similar to a candidate patient. We modeled four statin decisions for each patient: none, low-intensity, moderate-intensity, and high-intensity. For each candidate patient, the algorithm recommended the statin decision that was associated with the greatest percentage reduction in LDL-C after 1 year in similar patients. The overall cohort consisted of 50,576 patients (age 54.6 ± 9.8 years) with 55% female, 48% non-Hispanic White, 32% Asian, and 7.4% Hispanic patients. Among 8383 test-set patients, 52%, 44%, and 4% were recommended high-, moderate-, and low-intensity statins, respectively, for a maximum predicted average 1-yr LDL-C reduction of 16.9%, 20.4%, and 14.9%, in each group, respectively. Overall, using aggregate EHR data, a personalized statin recommendation approach identified the statin intensity associated with the greatest LDL-C reduction in historical patients similar to a candidate patient. Recommendations included low- or moderate-intensity statins for maximum LDL-C lowering in nearly half the test set, which is discordant with their expected guideline-based efficacy. A data-driven personalized statin recommendation approach may inform shared decision making in areas of uncertainty, and highlight unexpected efficacy-effectiveness gaps.

EP.TU.569Improving Confidence and Technique When Preparing Nipple Smears for Cytology

Abstract Aims To create a sustainable means of educating breast surgeons on how to prepare nipple smears for cytology when investigating nipple discharge. Methods A nation-wide questionnaire of 51 doctors conducted in 2020 identified low confidence and competency in preparing a nipple smear slide. A 3-minute training video was subsequently created and published to the Association of Breast Surgery (ABS) website for universal access. Doctors were prompted to complete a questionnaire after watching the video to assess understanding, confidence, and obtain video feedback. Results were collected and analysed using Qualtrics software. Results 31 doctors completed the survey (10% foundation doctors, 77% specialist trainees, 13% consultants). The mean±StD nipple smears prepared per year was 1.74±0.95. The percentage of doctors who felt confident in their technique increased from 44% to 100%. Ninety-seven per cent correctly identified how to store and label the sample, previously 45%. The percentage of doctors aware of where to place the sample on the slide increased from 37% to 100%. Eighty-seven per cent were aware of the optimal fluid volume in comparison to 10% previously. All respondents felt the video was valuable and 71% of respondents indicated they would also benefit from a written list of instructions. Conclusions The preparation of nipple smear slides has historically been an area of clinical uncertainty. An educational video was successfully created to educate all grades of doctors and made universally accessible through the ABS website.

Left ventricular ejection fraction as an imaging biomarker to guide cardiac resynchronisation therapy in heart failure patients: a multimodal comparison of 2D and 3D echocardiography and CMR

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): The authors acknowledge financial support from the Department of Health through the National Institute for Health Research (NIHR) comprehensive Biomedical Research Centre award to Guy’s & St Thomas’ NHS Foundation Trust in partnership with King’s College London and King’s College Hospital NHS Foundation Trust and by the NIHR MedTech Co-operative for Cardiovascular Disease at Guy’s and St Thomas’ NHS Foundation Trust. This work was supported by the Wellcome/EPSRC Centre for Medical Engineering [WT 203148/Z/16/Z]. MSN was funded by a clinical lectureship awarded by the NIHR. The views expressed are those of the authors and not necessarily those of the NHS, the NIHR, the DoH, EPSRC, MRC or the Wellcome Trust. Introduction – Imaging derived left ventricular ejection fraction (LVEF) has an important role to guide initiation of medical therapy and device insertion in patients with heart failure and reduced ejection fraction (HFrEF). Previous studies have reported the correlation and agreement of LVEF in various patient populations, but sparse evidence exists on patients with heart failure referred for Cardiac Resynchronisation Therapy (CRT) using 2D and 3D echocardiography (2DE & 3DE) and cardiovascular magnetic resonance (CMR). Objectives – To determine the correlation and agreement of LVEF as determined by 2DE, 3DE and CMR in a cohort of HF patients referred for assessment of CRT. Methods – Patients with suspected HFrEF referred for assessment for CRT therapy were included in this single centre study. Patients underwent 2DE, 3DE and CMR to derive LVEF, LVESV and LVEDV. Correlation was determined with Pearson’s correlation, agreement with Bland-Altman analysis and Cohen’s kappa analysis for agreement using a dichotomous cut off of LVEF ≤35% as a threshold for CRT insertion (Ponikowski, 2016). Results - 55 patients (mean age 71 ± 9.2, 76% male) were included. The mean LVEF for 2DE, 3DE, CMR and were 32.4 ± 8.6, 32.1 ± 9.6 and 30.3 ± 9.5 respectively. CMR had a significantly lower LVEF compared to 2DE (p = 0.03). There was good correlation between 3DE & CMR and 2DE & CMR, and excellent correlation between 3DE and 2DE for LVEF (Table 1). There was for trend for CMR to underestimate LVEF compared to 2DE and 3DE, with small biases although wide limits of agreement (Figure 1). There was excellent correlation of LVEDV and LVESV across all 3 techniques. CMR underestimated volumes compared to 2DE and 3DE with large biases and wide LOA. The kappa coefficient agreement at threshold level for CRT insertion (LVEF ≤35%) was fair for 3DE and CMR (0.379, p = 0.004) and 2DE and CMR (0.462, p = 0.001), and moderate for 3DE and 2DE (0.575, p ≤ 0.001). Conclusion – Whilst LVEF is not the only indicator to guide CRT insertion, it remains an important imaging parameter for clinical decision making. We observed large biases in left ventricular volumes between 2D, 3D and CMR. However, whilst the overall bias in LVEF is small, the wide limits of agreement (LOA) observed may represent an area of clinical uncertainty, which may impact on the dichotomous imaging threshold for CRT insertion. Comparison of indices between modalities LVEF Correlation (r) LVEF Bias & LOA (%±SD) EDV Correlation (r) EDV Bias & LOA (mL ± SD) ESV Correlation (r) ESV Bias & LOA (mL ± SD) 3DE vs CMR 0.676 (p < 0.001) +1.75 ± 15.4 0.896 (p < 0.001) -82.16 ± 42.8 0.937 (p < 0.001) -61.3 ± 34.9 3DE vs 2DE 0.872 (p < 0.001) +0.48 ± 4.5 0.909 (p < 0.001) -10.31 ± 28.3 0.936 (p < 0.001) -8.42 ± 20.5 2DE vs CMR 0.675 (p < 0.001) +2.35 ± 14.6 0.876 (p < 0.001) -67.35 ± 36.3 0.898 (p < 0.001) -51.42 ± 30.1 Abstract Figure. Bland-Altman Plot LVEF by 3DE & CMR

Sleep-disordered breathing in patients on opioids for chronic pain

The past two decades has seen a substantial rise in the use of opioids for chronic pain, along with opioid-related mortality and adverse effects. A contributor to opioid-associated mortality is...

Exploring the Basis and Acceptability of Practice Variation Among Thrombosis Medicine Specialists: A Mixed-Methods Study

Background: How physicians navigate the uncertainty of diagnosis and management of medical conditions with limited evidence is largely unknown. One lens to look at uncertainty in medicine is through evaluating practice variation among physicians, or their differences in their clinical management. Thrombosis medicine is a subspecialty that focuses on the diagnosis and management of patients with venous thromboembolism or its complications. By better defining the nature and acceptability of practice variation in thrombosis medicine, we can gain insights into how to improve patient care and education of learners in situations when uncertainty exists. Purpose: The aims of our study include: (1) Understand the quantity and type of variation that exists among thrombosis specialists; (2) Determine the level of acceptability of practice variation among thrombosis specialists and (3) Identify any guiding principles that thrombosis specialists used when making decisions in areas of clinical uncertainty. Methods: Five challenging clinical vignettes were presented to thrombosis specialists in Ottawa, Canada in 60 minute semi-structured interviews. The vignettes included the management of symptomatic superficial vein thrombosis, a pregnant patient with a pulmonary embolism, a patient with cirrhosis and a portal vein thrombosis, a patient with suspected Essential Thrombocythemia and a deep vein thrombosis, and a patient with past pregnancy losses and positive antiphospholipid antibodies. All management options described in the interviews were included in a follow-up anonymous online questionnaire to the same specialists, in order to delineate the acceptability of other specialists' answers. Interview data were audio recorded and transcribed. Themes were developed through open coding with constant comparative analysis, and through focused coding using the conceptual framework Principles and Preferences. Questionnaire data was analyzed with descriptive statistics, with means, standard deviations (SD) and ranges for continuous variables, and frequencies with percentages for dichotomous variables. Results: All ten (100%) thrombosis specialists completed interviews and 8 completed the follow-up survey. Out of 110 possible management options identified across 5 clinical vignettes, 88 (80%) management options were recommended by at least 1 thrombosis specialist. Complete consensus where all specialists recommended a management option was reached in only 3 (3.4%) items. Consensus, defined as >50% of participants recommending or strongly recommending a management option, was achieved in 23 (26%) of the management options. Despite wide practice variation, there was a high level of acceptability of the different management options. Analysis of interview data identified how specialists managed clinical uncertainty, which included five themes: (1) Knowing the latest evidence or relying on colleagues' expertise; (2) Past experiences; (3) Clinical gestalt and common sense; (4) "Benefits outweigh the risks" and (5) Improving the patient experience. Conclusions: While there was a wide range of practice variation among thrombosis specialists in cases of clinical uncertainty, there was a high level of acceptability of different management options. Research is needed on how this affects patient care and the instruction and assessment of learners. Disclosures No relevant conflicts of interest to declare.

Male infertility websites: what are our patients reading?

People ages 20-45 years (reproductive age) have been shown to use the Internet as a source of health information more frequently than their older counterparts. We sought to evaluate the quality and readability of highly visible websites on male infertility. Structured website review. Using Google, the first 60 relevant websites from the search “male infertility” were classified by source and analyzed. Content was evaluated by 4 blinded reviewers. We chose Google because it is the most widely used search engine, comprising 74.5% of Internet searches. Website quality of information was evaluated using the DISCERN score (assesses the quality of written information on treatment choices for a health problem), JAMA benchmark criteria (uses four core standards to evaluate web sites: authorship, attribution, disclosure, currency), and Health on the Net code (HONcode) accreditation status (assesses the reliability and credibility of online information). Readability was assessed using the Dale-Chall and Flesh Reading Ease indexes. Websites were classified as: 43% hospital based, 12% fertility clinic based, 5% other clinic based, 33% society/association based, and 7% government based. The mean total DISCERN score was 44 ± 12 (maximum score 80). 75% (45/60) of websites had clear aims or achieved their aims (scores of 4 or 5 [good]), but only 15% (9/60) described areas of clinical uncertainty. 25% (15/60) described the benefits of treatments, but only 5% (3/60) described the risks of treatments. 72% (43/60) provided unbiased information. 68% (41/60) websites made it clear that there was more than one possible treatment choice. 27% (16/60) of websites encouraged shared decision making. Overall, 60% (36/60) of websites were “poor quality” (score 1-2-3) on the final question of the DISCERN instrument. Only 4/60 (6.7%) websites met all four JAMA benchmark criteria. The mean Dale-Chall score was 9.53 +/- 1.30, indicating a college or graduate degree level of readability. The mean Flesh Reading Ease index was 34.01 +/- 16.26, indicating a graduate degree level of readability. 20% (12/60) of websites were HONcode certified. Websites on “male infertility” are of low quality, and only 6.7% met JAMA benchmark criteria. Minimal information on treatments was present, with only 25% of websites describing treatment benefits, but only 5% describing treatment risks. Only 15% of websites described areas of clinical uncertainty. Despite that these websites were written at a college to graduate degree level of reading, only 27% encouraged shared decision making. Reassuringly, most of these websites were hospital based, and 72% provided unbiased information. Patients should be cautioned that incomplete and potentially biased information on male infertility is prevalent online.

Effects of testosterone therapy for women: a systematic review and meta-analysis protocol

BackgroundTestosterone therapy for women is in widespread use, primarily in the form of compounded preparations and off-label use of formulations for men. The benefits and risks of such therapy remain uncertain. This review will identify and evaluate studies that have examined the effects of testosterone therapy for women on a range of outcomes including sexual function, cardiovascular events, metabolic parameters, musculoskeletal health, wellbeing, cancer events, androgenic effects and withdrawal rates.MethodsStudies meeting our pre-determined inclusion criteria will be identified through searches in Ovid MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials (CENTRAL) and Web of Science. Assessing a range of outcomes, we will assess the risk-of-bias of relevant studies and draw conclusions about the strength of evidence for benefits and risks of testosterone therapy for each outcome.DiscussionThis comprehensive systematic review with meta-analysis will provide the foundation for the development of evidence-based clinical practice guidelines that will address benefits and risks of testosterone therapy, when treatment might be appropriate or inappropriate, areas of clinical uncertainty and the basis for assessment and monitoring of patients.Systematic review registrationPROSPERO registration number: CRD42018104073

PP189 Filling In The Blanks: Is RWE From MAAs Used In NICE Decision Making?

IntroductionThe National Institute for Health and Care Excellence (NICE) may recommend temporary funding through managed access agreements (MAAs) for oncology drugs (via the Cancer Drugs Fund [CDF]) and highly specialized therapies for rare diseases. MAAs allow for the collection of evidence to address key areas of clinical uncertainty, while providing access of medicines to patients, prior to re-appraisal by NICE. Observational data and other real-world evidence (RWE) are crucial requirements for all MAAs and herein we examine the extent these data are being used to inform HTA decisions at re-appraisal.MethodsExisting MAAs entered into between the National Health Service (NHS) England and manufacturers as of 30 October 2018 were identified; for drug:indication pairings with NICE re-appraisals, all information was reviewed and the key data extracted.ResultsOf the twenty-two MAAs identified, only two drug:indication pairings have been subsequently re-appraised by NICE: BV(brentuximab vedotin):non-Hodgkin lymphoma (’recommended’) and pembrolizumab:relapsed or refractory classical Hodgkin lymphoma (’recommended’). Data from a retrospective questionnaire regarding the proportion of patients that received curative stem cell transplant (SCT) post-BV (from patients who received BV in the old CDF) were accepted to provide sufficient evidence on the post-BV SCT rate by NICE. Meanwhile, for pembrolizumab, long-term survival benefit was the key clinical uncertainty; the primary data collection source was updated phase III randomized controlled trial data. At re-appraisal no reference was made to the observational data component; more mature survival data reduced uncertainty over survival benefits and were sufficient to support a positive NICE recommendation.ConclusionsOf the twenty-two MAAs to date, only two drugs have been re-appraised thus far, with both receiving positive NICE recommendations. Observational data were successfully used to address key clinical uncertainties regarding subsequent real-world treatment patterns for BV, but observational data were not referred to in the NICE recommendation for pembrolizumab. The re-appraisal of more drugs in the future will clarify the importance being placed on observational data collection requested by NICE for existing MAAs.

Landmark trials in thrombotic vascular disease: a critical appraisal of potential practice-changing trials in 2016-2017.

Recent years have witnessed an onslaught of large, multicenter, randomized controlled trials evaluating the prevention and management of thrombotic vascular diseases. While these trials have applied rigorous methodology to pragmatic and clinically relevant questions, several important gaps in knowledge remain. In this review, we critically appraise landmark studies in thrombosis published between 2016 and 2017 that address several ongoing areas of clinical uncertainty. Specifically, we review the role of endovascular therapy in the prevention of post-thrombotic syndrome following acute lower limb deep vein thrombosis (DVT) (ATTRACT trial), the efficacy of edoxaban as the first direct oral anticoagulant used for the treatment of cancer-associated thrombosis (HOKUSAI VTE-Cancer study), whether aspirin can be considered for thromboprophylaxis post-major orthopedic surgery (EPCAT-2 trial), and the need for anticoagulant therapy for treatment of isolated distal DVT (CACTUS trial). Using illustrative cases, we highlight the applicability of these trials to current practice and emphasize the unanswered questions that remain.

Service evaluation project - Are local recommendations for onward referral to a specialist menopause clinic required to translate guidelines into practice?

Objective Referral audit - are local recommendations required to translate guideline to practice? Study design In total, 50 consecutive, anonymised referral letters reviewed during the initial consultation in a specialist menopause clinic; the reasons for referral along with the patient's age and the source of referral were analysed. Results Several common reasons for referral were identified. Sexual dysfunction, including loss of libido and dyspareunia, resulted in 11 (22%) referrals. Ten (20%) women were troubled by persistent symptoms or side effects from HRT; 9 (18%) women were referred before hormone replacement therapy was discussed or commenced; 7 (14%) women seeking advice for their menopausal symptoms had a family or personal history of cancer; 5(10%) were migraineurs; 2(4%) women had premature ovarian insufficiency; 2(4%) were denied hormone replacement therapy because of concern about venous thromboembolism risk; and 4 (8%) had miscellaneous medical disorders. Over 25% of referrals were older than 60. Conclusion Menopausal symptoms are predominately dealt with in primary care where advice and support is needed. National Institute for Health Care and Excellence published guidance regarding onward referral to a specialist menopause clinic, which is vague and referral patterns are haphazard. Our audit highlighted areas of clinical uncertainty and formed the basis for providing local pre-referral information and advice. Some of the information provided is quite detailed and aimed at healthcare professionals with a special interest in menopause. Further training is now required to improve the quality of referrals. The diversity and complexity of some referrals illustrates the need both for a menopause specialist and clear pathways for further advice or referral within each region.

Identifying the factors influencing practice variation in thrombosis medicine: A qualitative content analysis of published practice-pattern surveys

Practice variation, the differences in clinical management between physicians, is one reason why patient outcomes may differ. Identifying factors that contribute to practice variation in areas of clinical uncertainty or equipoise may have implications for understanding and improving patient care. To discern what factors may influence practice variation, we completed a qualitative content analysis of all practice-pattern surveys in thrombosis medicine in the last 10years. Out of 2117 articles screened using a systematic search strategy, 33 practice-pattern surveys met eligibility criteria. Themes were identified using constant comparative analysis of qualitative data. Practice variation was noted in all 33 practice-pattern surveys. Contributing factors to variation included lack of available evidence, lack of clear and specific guideline recommendations, past experience, patient context, institutional culture and the perceived risk and benefit of a particular treatment. Additional themes highlight the value placed on expertise in challenging clinical scenarios, the complexity of practice variation and the value placed on minimizing practice variation.

Factors that influence clinicians’ decisions to offer intravenous alteplase in acute ischemic stroke patients with uncertain treatment indication: Results of a discrete choice experiment

Background Treatment with intravenous alteplase for eligible patients with acute ischemic stroke is underused, with variation in treatment rates across the UK. This study sought to elucidate factors influencing variation in clinicians' decision-making about this thrombolytic treatment. Methods A discrete choice experiment using hypothetical patient vignettes framed around areas of clinical uncertainty was conducted with UK-based clinicians. Mixed logit regression analyses were conducted on the data. Results A total of 138 clinicians completed the discrete choice experiment. Seven patient factors were individually predictive of increased likelihood of immediately offering IV alteplase (compared to reference levels in brackets): stroke onset time 2 h 30 min [50 min]; pre-stroke dependency mRS 3 [mRS 4]; systolic blood pressure 185 mm/Hg [140 mm/Hg]; stroke severity scores of NIHSS 5 without aphasia, NIHSS 14 and NIHSS 23 [NIHSS 2 without aphasia]; age 85 [68]; Afro-Caribbean [white]. Factors predictive of withholding treatment with IV alteplase were: age 95 [68]; stroke onset time of 4 h 15 min [50 min]; severe dementia [no memory problems]; SBP 200 mm/Hg [140 mm/Hg]. Three clinician-related factors were predictive of an increased likelihood of offering IV alteplase (perceived robustness of the evidence for IV alteplase; thrombolyzing more patients in the past 12 months; and high discomfort with uncertainty) and one with a decreased likelihood (high clinician comfort with treating patients outside the licensing criteria). Conclusions Both patient- and clinician-related factors have a major influence on the use of alteplase to treat patients with acute ischemic stroke. Clinicians' views of the evidence, comfort with uncertainty and treating patients outside the license criteria are important factors to address in programs that seek to reduce variation in care quality regarding treatment with IV alteplase. Further research is needed to further understand the differences in clinical decision-making about treating patients with acute ischemic stroke with IV alteplase.

Factors that influence variation in clinical decision-making about thrombolysis in the treatment of acute ischaemic stroke: results of a discrete choice experiment

BackgroundIntravenous thrombolysis for patients with acute ischaemic stroke is underused (only 80% of eligible patients receive it) and there is variation in its use across the UK. Previously, variation might have been explained by structural differences; however, continuing variation may reflect differences in clinical decision-making regarding the eligibility of patients for treatment. This variation in decision-making could lead to the underuse, or result in inappropriate use, of thrombolysis.ObjectivesTo identify the factors which contribute to variation in, and influence, clinicians’ decision-making about treating ischaemic stroke patients with intravenous thrombolysis.MethodsA discrete choice experiment (DCE) using hypothetical patient vignettes framed around areas of clinical uncertainty was conducted to better understand the influence of patient-related and clinician-related factors on clinical decision-making. An online DCE was developed following an iterative five-stage design process. UK-based clinicians involved in final decision-making about thrombolysis were invited to take part via national professional bodies of relevant medical specialties. Mixed-logit regression analyses were conducted.ResultsA total of 138 clinicians responded and opted to offer thrombolysis in 31.4% of cases. Seven patient factors were individually predictive of the increased likelihood of offering thrombolysis (compared with reference levels in brackets): stroke onset time of 2 hours 30 minutes (50 minutes); pre-stroke dependency modified Rankin Scale score (mRS) of 3 (mRS4); systolic blood pressure (SBP) of 185 mmHg (140 mmHg); stroke severity scores of National Institutes of Health Stroke Scale (NIHSS) 5 without aphasia, NIHSS 14 and NIHSS 23 (NIHSS 2 without aphasia); age 85 years (65 years); and Afro-Caribbean (white). Factors predictive of not offering thrombolysis were age 95 years; stroke onset time of 4 hours 15 minutes; severe dementia (no memory problems); and SBP of 200 mmHg. Three clinician-related factors were predictive of an increased likelihood of offering thrombolysis (perceived robustness of the evidence for thrombolysis; thrombolysing more patients in the past 12 months; and high discomfort with uncertainty) and one factor was predictive of a decreased likelihood of offering treatment (clinicians’ being comfortable treating patients outside the licensing criteria).LimitationsWe anticipated a sample size of 150–200. Nonetheless, the final sample of 138 is good considering that the total population of eligible UK clinicians is relatively small. Furthermore, data from the Royal College of Physicians suggest that our sample is representative of clinicians involved in decision-making about thrombolysis.ConclusionsThere was considerable heterogeneity among respondents in thrombolysis decision-making, indicating that clinicians differ in their thresholds for treatment across a number of patient-related factors. Respondents were significantly more likely to treat 85-year-old patients than patients aged 68 years and this probably reflects acceptance of data from Third International Stroke Trial that report benefit for patients aged > 80 years. That respondents were more likely to offer thrombolysis to patients with severe stroke than to patients with mild stroke may indicate uncertainty/concern about the risk/benefit balance in treatment of minor stroke. Findings will be disseminated via peer-review publication and presentation at national/international conferences, and will be linked to training/continuing professional development (CPD) programmes.Future workThe nature of DCE design means that only a subset of potentially influential factors could be explored. Factors not explored in this study warrant future research. Training/CPD should address the impact of non-medical influences on decision-making using evidence-based strategies.FundingThe National Institute for Health Research Health Services and Delivery Research programme.

Spotlight on real-world evidence for the treatment of DVT: XALIA.

Venous thromboembolism (VTE), comprising both deep-vein thrombosis (DVT) and pulmonary embolism (PE), is a serious and common cardiovascular disease associated with the risk of chronic complications, recurrent VTE events and even death. The treatment landscape has, in recent years, seen a paradigm shift from the use of traditional anticoagulants (low-molecular-weight heparin [LMWH] overlapping with and followed by a vitamin K antagonist [VKA]) to non-VKA oral anticoagulants (NOACs). This class of agents, encompassing direct factor Xa inhibitors and direct thrombin inhibitors have shown non-inferior efficacy and better safety to standard of care in randomised controlled trials (RCTs). The direct, oral factor Xa inhibitor rivaroxaban was the first to be approved for treatment of acute DVT and PE and secondary prevention of recurrent VTE events based on data from EINSTEIN DVT and EINSTEIN PE, respectively. Real-world evidence now helps to further support data from RCTs, and also bridges the gap for physicians regarding any areas of clinical uncertainty that may not be addressed by RCTs. XA inhibition with rivaroxaban for Long-term and Initial Anticoagulation in venous thromboembolism (XALIA) was the first large, prospective, observational, real-world study that has investigated the safety and effectiveness profile of rivaroxaban in patients with DVT and PE associated with DVT in routine clinical practice. This article will present the key clinical outcomes from this important global non-interventional study, and will discuss remaining questions to be addressed in Phase IV studies.

How should we manage information needs, family anxiety, depression, and breathlessness for those affected by advanced disease: development of a Clinical Decision Support Tool using a Delphi design.

BackgroundClinicians request guidance to aid the routine use and interpretation of Patient Reported Outcome Measures (PROMs), but tools are lacking. We aimed to develop a Clinical Decision Support Tool (CDST) focused on information needs, family anxiety, depression, and breathlessness (measured using the Palliative care Outcome Scale (POS)) and related PROM implementation guidance.MethodsWe drafted recommendations based on findings from systematic literature searches. In a modified online Delphi study, 38 experts from 12 countries with different professional backgrounds, including four patient/carer representatives, were invited to rate the appropriateness of these recommendations for problems of varying severity in the CDST. The quality of evidence was added for each recommendation, and the final draft CDST reappraised by the experts. The accompanying implementation guidance was built on data from literature scoping with expert revision (n = 11 invited experts).ResultsThe systematic literature searches identified over 560 potential references, of which 43 met the inclusion criteria. Two Delphi rounds (response rate 66 % and 62 %; n = 25 and 23) found that good patient care, psychosocial support and empathy, and open communication were central to supporting patients and families affected by all POS concerns as a core requirement. Assessment was recommended for increasing problems (i.e. scores), followed by non-pharmacological interventions and for breathlessness and depression, pharmacological interventions. Accompanying PROM implementation guidance was built based on the 8-step International Society for Quality of Life Research framework, as revised by nine (response rate 82 %) experts.ConclusionsThis CDST provides a straightforward guide to help support clinical care and improve evidence-based outcomes for patients with progressive illness and their families, addressing four areas of clinical uncertainty. Recommendations should be used flexibly, alongside skilled individual clinical assessment and knowledge, taking into account patients’ and families’ individual preferences, circumstances, and resources. The CDST is provided with accompanying implementation guidance to facilitate PROM use and is ready for further development and evaluation.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0449-6) contains supplementary material, which is available to authorized users.

Abstract 2506: Differentiating pancreatic cystic neoplasms by global protease specificity

Abstract Decision-making for patients with pancreatic cystic lesions represents the greatest area of clinical uncertainty in the management of pancreatic disease today. Short of pancreas removal, there is no definitive technology that differentiates benign, pre- malignant, and malignant pancreatic cystic neoplasms. As a result, some patients die from undiagnosed cancers, while others undergo unnecessary pancreatic resections with considerable morbidity. The cyst fluid from these neoplasms is a rich resource for the discovery of new biomarkers because it is in direct contact with the involved cells, and it is sampled routinely as a part of clinical care. Amylase activity and CEA concentration are typically measured, but they lack prognostic value. Protein levels of proteases and their inhibitors differ between benign and malignant cystic neoplasms, however, effects on enzymatic activity and specificity profiles are unknown. We sought to identify and characterize proteolytic signatures specific to different stages of pancreatic carcinogenesis. We used a new protease substrate profiling technology recently developed in our lab, Multiplex Substrate-Profiling by Mass Spectrometry (MSP-MS), that can detect and classify the specificity of endo- and exopeptidases in a complex sample. This assay consists of a physiochemically diverse library of 228 tetradecapeptides designed by incorporating all combinations of neighbor and near-neighbor amino acid pairs to provide maximum specificity information. We have previously used this technology to determine the “proteolytic signatures” of mouse pancreatic cancer cell secretions and human neutrophil extracellular traps. MSP-MS has the unique ability to monitor all peptide bonds cleaved from this library of peptides, thereby simultaneously detecting aminopeptidase, carboxypeptidase and endopeptidase activity. This assay was applied to pancreatic cyst fluid derived from 4 low risk and 4 high risk lesions as determined by current clinical guidelines. The cleavage data from the respective categories was combined and compared. The proteases in the samples generated 773 cleavage sites in the low risk category and only 285 in the high risk category. Interestingly, only 220 of the sites were shared between groups. The signature from the low risk group had a trypsin-like specificity with arginine and lysine preferred at the P1 position, whereas the high risk group had minimal trypsin-like specificity and predominantly showed amino- and carboxypeptidase activity. These data suggest that protease profiling of pancreatic cyst fluid may facilitate risk stratification among pancreatic cystic lesions and thereby guide clinical decision-making. MSP-MS offers a unique technology to both identify active proteases in clinical samples of interest and measure total and specific proteolytic activity despite the presence of endogenous inhibitors. Citation Format: Dana A. Dominguez, Anthony J. O'Donoghue, Kimberly S. Kirkwood, Charles S. Craik. Differentiating pancreatic cystic neoplasms by global protease specificity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2506. doi:10.1158/1538-7445.AM2014-2506

Contemporary splinting practice in the UK for adults with neurological dysfunction: A cross-sectional survey

Aim: To explore the contemporary splinting practice of UK occupational therapists and physiotherapists for adults with neurological dysfunction. Method: Cross-sectional online survey of members of the Association of Chartered Physiotherapists in Neurology and College of Occupational Therapists Specialist Section Neurological Practice. Results: Four hundred and twenty therapists completed the survey. Contracture management is the most common rationale for therapists splinting adults with neurological dysfunction. Other shared therapeutic goals of splinting include maintaining muscle and joint alignment, spasticity management, function, pain management and control of oedema. Considerable clinical uncertainty was uncovered in practice particularly around wearing regimens of splints. Most therapists have access to locally-derived splinting guidelines, which may contribute to this diversity of practice. Conclusions: This study provides a unique insight into aspects of contemporary splinting practice among UK therapists, who belong to a specialist neurological professional network and work in a number of different health-care settings with adults who have a neurological condition. Study findings show a wide variation in splinting practice, thereby indicating a potential need for national guidance to assist therapists in this area of clinical uncertainty. Further research is required to establish best practice parameters for splinting in neurological rehabilitation.

Clinical Decision Making when Addressing Upper Limb Post-Stroke Sensory Impairments

Introduction: This study explored factors influencing occupational therapists' clinical decision making when choosing to assess upper limb post-stroke sensory impairments (ULPSSI) and selecting interventions. Method: A survey of 187 American occupational therapists working with stroke survivors. Findings: Respondents most commonly assessed ULPSSI to determine the impact on occupational performance and guide interventions, and most commonly did not undertake assessment if clients either reported no impairments or were unable to participate in testing. Being unaware of interventions, believing motor interventions addressed ULPSSI and lack of time most commonly led to the decision not to use interventions for ULPSSI. Clients' cognitive status, severity of ULPSSI and time since stroke influenced therapists when choosing between compensatory or remedial approaches. Prior experience, effects seen when trialling interventions and consulting other therapists most commonly influenced specific intervention choice. Conclusion: Deciding to assess ULPSSI was influenced by theoretical knowledge and domain-specific clinical knowledge while decisions about interventions were largely influenced by the therapists' domain-specific clinical knowledge, clinical experience and by specific contextual factors such as time available for therapy. Respondents used both automatic and reflective or deliberate decision-making processes. Education on evidence-based interventions and strategies for decision making in areas of clinical uncertainty is warranted.