Pulmonary embolism and mortality following total ankle replacement: a data linkage study using the NJR data set

OBJECTIVE: To determine the mortality rate following total ankle replacement (TAR) and incidence of 90 day pulmonary embolism (PE) along with the associated risk factors.  DESIGN: Data-linkage study of the UK National Joint Registry (NJR) data and Hospital Episodes Statistics (HES) database. Linkage was performed in a deterministic fashion. HES episodes 90 days after the index procedure were analysed for PE. Mortality data were obtained pertaining to all the index procedures from the NJR for analysis.  PARTICIPANTS: All primary and revision ankle replacement patients captured on the NJR between February 2008 and February 2013.  RESULTS: The 90-day mortality following TAR was 0.13% (95% CI 0.03 to 0.52) and 1-year mortality was 0.72% (95% CI 0.40 to 1.30); no deaths were as a result of PE. The incidence of PE within 90 days following primary TAR was 0.51% (95% CI 0.23 to 1.13). There was only one PE following revision surgery. Patients with an Royal College of Surgeons Charlson score greater than zero were at 13 times greater risk of PE (p=0.003).  CONCLUSIONS: There is low incidence of PE following TAR, but multiple comorbidities are a leading risk factor for its occurrence

Eliminating ambiguous treatment effects using estimands

Most reported treatment effects in medical research studies are ambiguously defined, which can lead to misinterpretation of study results. This is because most studies do not attempt to describe what the treatment effect represents, and instead require readers to deduce this based on the reported statistical methods. However, this approach is fraught, as many methods provide counterintuitive results. For example, some methods include data from all patients, yet the resulting treatment effect applies only to a subset of patients, whereas other methods will exclude certain patients while results will apply to everyone. Additionally, some analyses provide estimates pertaining to hypothetical settings where patients never die or discontinue treatment. Herein we introduce estimands as a solution to the aforementioned problem. An estimand is a clear description of what the treatment effect represents, thus saving readers the necessity of trying to infer this from study methods and potentially getting it wrong. We provide examples of how estimands can remove ambiguity from reported treatment effects and describe their current use in practice. The crux of our argument is that readers should not have to infer what investigators are estimating; they should be told explicitly

Rehabilitation following surgery for lumbar spinal stenosis: a Cochrane review

Study Design A systematic review of randomised controlled trials (RCTs) Objective To determine the effects of active rehabilitation on functional outcome following lumbar spinal stenosis surgery when compared with 'usual postoperative care'. Summary of background data Surgery rates for lumbar spinal stenosis have risen, yet outcomes remain suboptimal. Post-operative rehabilitation has been suggested as a tool to improve post-operative function but, to date, there is limited evidence to support its use. Methods CENTRAL (The Cochrane Library), the Cochrane Back Review Group Trials Register, MEDLINE, EMBASE, CINAHL and PEDro electronic databases were searched. Randomised controlled trials (RCTs) comparing the effectiveness of active rehabilitation with usual care in adults with lumbar spinal stenosis who had undergone primary spinal decompression surgery were included. Two authors independently selected studies, assessed the risk of bias, and extracted the data in line with the recommendations of the Cochrane Back Review Group. Study results were pooled in a meta-analysis when appropriate using functional status as the primary outcome, with secondary outcomes including measures of leg pain, low back pain, and global improvement/general health. The GRADE approach was used to assess the quality of the evidence. Results Our searches yielded 1,726 articles, of which three studies (N = 373 participants) were suitable for inclusion in meta-analysis. All included studies were deemed to have low risk of bias; no study had unacceptably high dropout rates. There was moderate evidence suggesting that active rehabilitation was more effective than usual care in improving both short- and long-term functional status following surgery. Similar findings were noted for secondary outcomes, including short-term improvement in low back pain and long-term improvement in both low back pain and leg pain. Conclusions We obtained moderate-quality evidence indicating that postoperative active rehabilitation after decompression surgery for lumbar spinal stenosis is more effective than usual care. Further work is required particularly with respect to the cost effectiveness of such interventions

A four-step strategy for handling missing outcome data in randomised trials affected by a pandemic.

BACKGROUND: The coronavirus pandemic (Covid-19) presents a variety of challenges for ongoing clinical trials, including an inevitably higher rate of missing outcome data, with new and non-standard reasons for missingness. International drug trial guidelines recommend trialists review plans for handling missing data in the conduct and statistical analysis, but clear recommendations are lacking. METHODS: We present a four-step strategy for handling missing outcome data in the analysis of randomised trials that are ongoing during a pandemic. We consider handling missing data arising due to (i) participant infection, (ii) treatment disruptions and (iii) loss to follow-up. We consider both settings where treatment effects for a 'pandemic-free world' and 'world including a pandemic' are of interest. RESULTS: In any trial, investigators should; (1) Clarify the treatment estimand of interest with respect to the occurrence of the pandemic; (2) Establish what data are missing for the chosen estimand; (3) Perform primary analysis under the most plausible missing data assumptions followed by; (4) Sensitivity analysis under alternative plausible assumptions. To obtain an estimate of the treatment effect in a 'pandemic-free world', participant data that are clinically affected by the pandemic (directly due to infection or indirectly via treatment disruptions) are not relevant and can be set to missing. For primary analysis, a missing-at-random assumption that conditions on all observed data that are expected to be associated with both the outcome and missingness may be most plausible. For the treatment effect in the 'world including a pandemic', all participant data is relevant and should be included in the analysis. For primary analysis, a missing-at-random assumption - potentially incorporating a pandemic time-period indicator and participant infection status - or a missing-not-at-random assumption with a poorer response may be most relevant, depending on the setting. In all scenarios, sensitivity analysis under credible missing-not-at-random assumptions should be used to evaluate the robustness of results. We highlight controlled multiple imputation as an accessible tool for conducting sensitivity analyses. CONCLUSIONS: Missing data problems will be exacerbated for trials active during the Covid-19 pandemic. This four-step strategy will facilitate clear thinking about the appropriate analysis for relevant questions of interest

A randomised, multi-centre trial of total ankle replacement versus ankle arthrodesis in the treatment of patients with end stage ankle osteoarthritis (TARVA): statistical analysis plan.

BACKGROUND: The total ankle replacement versus ankle arthrodesis (TARVA) trial aims to determine which surgical procedure confers the greatest improvement in pain-free function for patients with end-stage ankle osteoarthritis. Both procedures are effective but there has not yet been a direct comparison to establish which is superior. This article describes the statistical analysis plan for this trial as an update to the published protocol. It is written prior to the end of patient follow-up, while the outcome of the trial is still unknown. DESIGN AND METHODS: TARVA is a randomised, un-blinded, parallel group trial of total ankle replacement versus ankle arthrodesis. The primary outcome is the Manchester-Oxford Foot Questionnaire walking/standing domain score at 52 weeks post-surgery. Secondary outcomes include measures of pain, social interaction, physical function, quality of life, and range of motion. We describe in detail the statistical aspects of TARVA: the outcome measures, the sample size calculation, general analysis principles including treatment of missing data, the planned descriptive statistics and statistical models, and planned subgroup and sensitivity analyses. DISCUSSION: The TARVA statistical analysis will provide comprehensive and precise information on the relative effectiveness of the two treatments. The plan will be implemented in January 2020 when follow-up for the trial is completed. TRIAL REGISTRATION: ISRCTN registry number 60672307, ClinicalTrials.gov registration number NCT02128555. Registered 1 May 2014. Recruitment started in January 2015 and ended in January 2019

Starting a conversation about estimands with public partners involved in clinical trials: a co-developed tool

BACKGROUND: Clinical trials aim to draw conclusions about the effects of treatments, but a trial can address many different potential questions. For example, does the treatment work well for patients who take it as prescribed? Or does it work regardless of whether patients take it exactly as prescribed? Since different questions can lead to different conclusions on treatment benefit, it is important to clearly understand what treatment effect a trial aims to investigate-this is called the 'estimand'. Using estimands helps to ensure trials are designed and analysed to answer the questions of interest to different stakeholders, including patients and public. However, there is uncertainty about whether patients and public would like to be involved in defining estimands and how to do so. Public partners are patients and/or members of the public who are part of, or advise, the research team. We aimed to (i) co-develop a tool with public partners that helps explain what an estimand is and (ii) explore public partner's perspectives on the importance of discussing estimands during trial design. METHODS: An online consultation meeting was held with 5 public partners of mixed age, gender and ethnicities, from various regions of the UK. Public partner opinions were collected and a practical tool describing estimands, drafted before the meeting by the research team, was developed. Afterwards, the tool was refined, and additional feedback sought via email. RESULTS: Public partners want to be involved in estimand discussions. They found an introductory tool, to be presented and described to them by a researcher, helpful for starting a discussion about estimands in a trial design context. They recommended storytelling, analogies and visual aids within the tool. Four topics related to public partners' involvement in defining estimands were identified: (i) the importance of addressing questions that are relevant to patients and public in trials, (ii) involving public partners early on, (iii) a need for education and communication for all stakeholders and (iv) public partners and researchers working together. CONCLUSIONS: We co-developed a tool for researchers and public partners to use to facilitate the involvement of public partners in estimand discussions

A dose-finding design for dual-agent trials with patient-specific doses for one agent with application to an opiate detoxification trial.

There is a growing interest in early phase dose-finding clinical trials studying combinations of several treatments. While the majority of dose finding designs for such setting were proposed for oncology trials, the corresponding designs are also essential in other therapeutic areas. Furthermore, there is increased recognition of recommending the patient-specific doses/combinations, rather than a single target one that would be recommended to all patients in later phases regardless of their characteristics. In this paper, we propose a dose-finding design for a dual-agent combination trial motivated by an opiate detoxification trial. The distinguishing feature of the trial is that the (continuous) dose of one compound is defined externally by the clinicians and is individual for every patient. The objective of the trial is to define the dosing function that for each patient would recommend the optimal dosage of the second compound. Via a simulation study, we have found that the proposed design results in high accuracy of individual dose recommendation and is robust to the model misspecification and assumptions on the distribution of externally defined doses

The interleukin 1 receptor antagonist anakinra to reduce disease severity of palmoplantar pustulosis in adults: APRICOT RCT and PLUM mechanistic study

Background: Palmoplantar pustulosis is a rare, debilitating, chronic skin disease involving the hands and feet, and there are limited treatment options. Mechanistic findings suggest that interleukin 1 may be a pathogenic driver. // Objective: To determine whether or not anakinra [Sobi (Swedish Orphan Biovitrum AB), Stockholm, Sweden], an interleukin 1 receptor antagonist, delivers therapeutic benefit in palmoplantar pustulosis. // Design: A Phase IV, randomised, double-blind, placebo-controlled study with two stages and an adaptive element (24 participants in stage 1, 64 participants in total) with an open-label extension. // Setting: Sixteen hospitals across England, Scotland and Wales. // Participants: Adults (aged ≥ 18 years) with a diagnosis of palmoplantar pustulosis and a disease duration of > 6 months and of sufficient impact and severity to require systemic therapy. // Interventions Participants were randomised (1 : 1) to daily self-administered subcutaneous injection of either anakinra or a placebo for 8 weeks. Main outcome measures The primary outcome was the Palmoplantar Pustulosis Area and Severity Index score measured at 0, 1, 4, 8 and 12 weeks, with the primary end point at 8 weeks adjusted for baseline. Secondary outcomes included other investigator-assessed efficacy measures of disease severity, safety measures and participant-reported measures of efficacy and impact. Results A total of 64 participants (mean baseline Palmoplantar Pustulosis Area and Severity Index score of 17.8, standard deviation 10.5) received anakinra (n = 31) or the placebo (n = 33). In the primary intention-to-treat analysis, which estimated the effect of the treatment policy, the mean treatment group difference at 8 weeks after adjustment for baseline Palmoplantar Pustulosis Area and Severity Index score was –1.65 (95% confidence interval –4.77 to 1.47; p = 0.300), in favour of anakinra relative to placebo, but was not statistically significant. Similarly, secondary investigator-assessed outcomes did not show statistical superiority of anakinra: the baseline-adjusted mean difference in fresh pustule count (palms and soles) between the anakinra group and the placebo group was 2.94 (95% confidence interval –26.44 to 32.33), in favour of placebo, and the mean difference in total pustule count was –30.08 (95% confidence interval –83.20 to 23.05), in favour of anakinra. Participant-assessed outcomes were consistent with these objective findings: the baseline-adjusted mean difference in Dermatology Life Quality Index between the anakinra group and the placebo group was 0.52 (95% confidence interval –2.04 to 3.07), in favour of placebo, and the mean difference in Palmoplantar Quality-of-Life Index was 1.27 (95% confidence interval –3.04 to 5.57), in favour of placebo. However, the proportion of participants who strongly agreed that treatment was worthwhile was greater in the anakinra group (12/29, 41%) than in the placebo group (4/28, 14%), a difference in proportion of 27% (95% confidence interval 5% to 49%). In the complier-average causal effect analysis, the baseline-adjusted mean treatment group difference in the week 8 Palmoplantar Pustulosis Area and Severity Index score in individuals who received ≥ 50% of injections was –2.30 (95% confidence interval –6.54 to 1.93; p = 0.287) and in those who received ≥ 90% of injections was –3.80 (95% confidence interval –10.76 to 3.16; p = 0.285), in favour of anakinra. No serious infections, significant neutropenia or other serious adverse events occurred. Injection site reactions were more frequent for those receiving anakinra (19/31, 61%) than for those receiving placebo (1/33, 3%). // Conclusions: There was no evidence that anakinra was superior to placebo. For the treatment of palmoplantar pustulosis, interleukin 1 blockade is not a useful intervention. // Limitations: The sample size was calculated to detect a large effect size. Treatment adherence was lower than expected. It cannot be ruled out that there was some selection bias towards less severe or unstable participants entering the trial given that the trial was placebo controlled with a required washout period. // Future work: Palmoplantar pustulosis remains an area of high unmet need and further research is recommended to (1) identify new drug targets, (2) determine the contributory role of drug exposure (including pharmacokinetics and adherence) and (3) validate outcome measures in palmoplantar pustulosis. // Trial registration: This trial is registered as ISCRTN13127147 and EudraCT 2015-003600-23. // Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 2. See the NIHR Journals Library for further project information

Sensitivity analysis for clinical trials with missing continuous outcome data using controlled multiple imputation: a practical guide

Missing data due to loss to follow‐up or intercurrent events are unintended, but unfortunately inevitable in clinical trials. Since the true values of missing data are never known, it is necessary to assess the impact of untestable and unavoidable assumptions about any unobserved data in sensitivity analysis. This tutorial provides an overview of controlled multiple imputation (MI) techniques and a practical guide to their use for sensitivity analysis of trials with missing continuous outcome data. These include δ ‐ and reference‐based MI procedures. In δ ‐based imputation, an offset term, δ , is typically added to the expected value of the missing data to assess the impact of unobserved participants having a worse or better response than those observed. Reference‐based imputation draws imputed values with some reference to observed data in other groups of the trial, typically in other treatment arms. We illustrate the accessibility of these methods using data from a pediatric eczema trial and a chronic headache trial and provide Stata code to facilitate adoption. We discuss issues surrounding the choice of δ in δ ‐based sensitivity analysis. We also review the debate on variance estimation within reference‐based analysis and justify the use of Rubin's variance estimator in this setting, since as we further elaborate on within, it provides information anchored inference