Development of guidelines to reduce, handle and report missing data in palliative care trials: A multi-stakeholder modified nominal group technique.

BACKGROUND: Missing data can introduce bias and reduce the power, precision and generalisability of study findings. Guidelines on how to address missing data are limited in scope and detail, and poorly implemented. AIM: To develop guidelines on how best to (i) reduce, (ii) handle and (iii) report missing data in palliative care clinical trials. DESIGN: Modified nominal group technique. SETTING/PARTICIPANTS: Patient and public research partners, palliative care clinicians, trialists, methodologists and statisticians attended a 1-day workshop, following which a multi-stakeholder development group drafted the guidelines. RESULTS: Seven main recommendations for reducing missing data, nine for handling missing data and twelve for reporting missing data were developed. The top five recommendations were: (i) train all research staff on missing data, (ii) prepare for missing data at the trial design stage, (iii) address missing data in the statistical analysis plan, (iv) collect the reasons for missing data and (v) report descriptive statistics comparing the baseline characteristics of those with missing and observed data. Reducing missing data, preparing for missing data and understanding the reasons for missing data were greater priorities for stakeholders than how to deal with missing data once they had occurred. CONCLUSION: Comprehensive guidelines on how to address missing data were developed by stakeholders involved in palliative care trials. Implementation of the guidelines will require endorsement of research funders and research journals.

Performance status and trial site-level factors are associated with missing data in palliative care trials: An individual participant-level data analysis of 10 phase 3 trials.

BACKGROUND: Missing data compromise the internal and external validity of trial findings, however there is limited evidence on how best to reduce missing data in palliative care trials. AIM: To assess the association between participant and site level factors and missing data in palliative care trials. DESIGN AND SETTING: Individual participant-level data analysis of 10 phase 3 palliative care trials using multi-level cross-classified models. RESULTS: Participants with missing data at the previous time-point and poorer performance status were more likely to have missing data for the primary outcome and quality of life outcomes, at the primary follow-up point and end of follow-up. At the end of follow-up, the number of site randomisations and number of study site personnel were significantly associated with missing data. Trial duration and the number of research personnel explained most of the variance at the trial and site-level respectively, except for the primary outcome where the amount of data requested was most important at the trial-level. Variance at the trial level was more substantial than at the site level across models and considerable variance remained unexplained for all models except quality of life at the end of follow-up. CONCLUSION: Participants with a poorer performance status are at higher risk of missing data in palliative care trials and require additional support to provide complete data. Performance status is a potential auxiliary variable for missing data imputation models. Reducing trial variability should be prioritised and further factors need to be identified and explored to explain the residual variance.

Intention-to-Treat Analyses for Randomized Controlled Trials in Hospice/Palliative Care: The Case for Analyses to be of People Exposed to the Intervention.

CONTEXT: Minimizing bias in randomized controlled trials (RCTs) includes intention-to-treat analyses. Hospice/palliative care RCTs are constrained by high attrition unpredictable when consenting, including withdrawals between randomization and first exposure to the intervention. Such withdrawals may systematically bias findings away from the new intervention being evaluated if they are considered nonresponders. OBJECTIVES: This study aimed to quantify the impact within intention-to-treat principles. METHODS: A theoretical model was developed to assess the impact of withdrawals between randomization and first exposure on study power and effect sizes. Ten reported hospice/palliative care studies had power recalculated accounting for such withdrawal. RESULTS: In the theoretical model, when 5% of withdrawals occurred between randomization and first exposure to the intervention, change in power was demonstrated in binary outcomes (2.0%-2.2%), continuous outcomes (0.8%-2.0%), and time-to-event outcomes (1.6%-2.0%), and odds ratios were changed by 0.06-0.17. Greater power loss was observed with larger effect sizes. Withdrawal rates were 0.9%-10% in the 10 reported RCTs, corresponding to power losses of 0.1%-2.2%. For studies with binary outcomes, withdrawal rates were 0.3%-1.2% changing odds ratios by 0.01-0.22. CONCLUSION: If blinding is maintained and all interventions are available simultaneously, our model suggests that excluding data from withdrawals between randomization and first exposure to the intervention minimizes one bias. This is the safety population as defined by the International Committee on Harmonization. When planning for future trials, minimizing the time between randomization and first exposure to the intervention will minimize the problem. Power should be calculated on people who receive the intervention.

Quality of missing data reporting and handling in palliative care trials demonstrates that further development of the CONSORT statement is required: a systematic review.

OBJECTIVES: Assess (i) the quality of reporting and handling of missing data (MD) in palliative care trials, (ii) whether there are differences in the reporting of criteria specified by the Consolidated Standards of Reporting Trials (CONSORT) 2010 statement compared with those not specified, and (iii) the association of the reporting of MD with journal impact factor and CONSORT endorsement status. STUDY DESIGN AND SETTING: Systematic review of palliative care randomized controlled trials. CENTRAL, MEDLINE, and EMBASE (2009-2014) were searched. RESULTS: One hundred and eight trials (15,560 participants) were included. MD was incompletely reported and not handled in accordance with current guidance. Reporting criteria specified by the CONSORT statement were better reported than those not specified (participant flow, 69%; number of participants not included in the primary outcome analysis, 94%; and the reason for MD, 71%). However, MD in items contributing to scale summaries (10%) and secondary outcomes (9%) were poorly reported, so the proportion of MD stated is likely to be an underestimate. The reason for MD provided was unclear for 54% of participants and only 16% of trials with MD reported a MD sensitivity analysis. The odds of reporting most of the MD and other risk of bias reporting criteria were increased as the journal impact factor increased and in journals that endorsed the CONSORT statement. CONCLUSION: Further development of the CONSORT MD reporting guidance is likely to improve the quality of reporting. Reporting recommendations are provided.

Missing data in randomized controlled trials testing palliative interventions pose a significant risk of bias and loss of power: a systematic review and meta-analyses.

OBJECTIVES: To assess the risk posed by missing data (MD) to the power and validity of trials evaluating palliative interventions. STUDY DESIGN AND SETTING: A systematic review of MD in published randomized controlled trials (RCTs) of palliative interventions in participants with life-limiting illnesses was conducted, and random-effects meta-analyses and metaregression were performed. CENTRAL, MEDLINE, and EMBASE (2009-2014) were searched with no language restrictions. RESULTS: One hundred and eight RCTs representing 15,560 patients were included. The weighted estimate for MD at the primary endpoint was 23.1% (95% confidence interval [CI] 19.3, 27.4). Larger MD proportions were associated with increasing numbers of questions/tests requested (odds ratio [OR], 1.19; 95% CI 1.05, 1.35) and with longer study duration (OR, 1.09; 95% CI 1.02, 1.17). Meta-analysis found evidence of differential rates of MD between trial arms, which varied in direction (OR, 1.04; 95% CI 0.90, 1.20; I(2) 35.9, P = 0.001). Despite randomization, MD in the intervention arms (vs. control) were more likely to be attributed to disease progression unrelated to the intervention (OR, 1.31; 95% CI 1.02, 1.69). This was not the case for MD due to death (OR, 0.92; 95% CI 0.78, 1.08). CONCLUSION: The overall proportion and differential rates and reasons for MD reduce the power and potentially introduce bias to palliative care trials.

Patient and health care professional decision-making to commence and withdraw from renal dialysis: a systematic review of qualitative research.

BACKGROUND AND OBJECTIVE: To ensure that decisions to start and stop dialysis in ESRD are shared, the factors that affect patients and health care professionals in making such decisions must be understood. This systematic review sought to explore how and why different factors mediate the choices about dialysis treatment. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: MEDLINE, Embase, CINAHL, and PsychINFO were searched for qualitative studies of factors that affect patients' or health care professionals' decisions to commence or withdraw from dialysis. A thematic synthesis was conducted. RESULTS: Of 494 articles screened, 12 studies (conducted from 1985 to 2014) were included. These involved 206 patients (most receiving hemodialysis) and 64 health care professionals (age ranges: patients, 26-93 years; professionals, 26-61 years). For commencing dialysis, patients based their choice on "gut instinct," as well as deliberating over the effect of treatment on quality of life and survival. How individuals coped with decision-making was influential: Some tried to take control of the problem of progressive renal failure, whereas others focused on controlling their emotions. Health care professionals weighed biomedical factors and were led by an instinct to prolong life. Both patients and health care professionals described feeling powerless. With regard to dialysis withdrawal, only after prolonged periods on dialysis were the realities of life on dialysis fully appreciated and past choices questioned. By this stage, however, patients were physically dependent on treatment. As was seen with commencing dialysis, individuals coped with treatment withdrawal in a problem- or emotion-controlling way. Families struggled to differentiate between choosing versus allowing death. Health care teams avoided and queried discussions regarding dialysis withdrawal. Patients, however, missed the dialogue they experienced during predialysis education. CONCLUSIONS: Decision-making in ESRD is complex and dynamic and evolves over time and toward death. The factors at work are multifaceted and operate differently for patients and health professionals. More training and research on open communication and shared decision-making are needed.

Comparison of survival analysis and palliative care involvement in patients aged over 70 years choosing conservative management or renal replacement therapy in advanced chronic kidney disease.

BACKGROUND: There are limited data on the outcomes of elderly patients with chronic kidney disease undergoing renal replacement therapy or conservative management. AIMS: We aimed to compare survival, hospital admissions and palliative care access of patients aged over 70 years with chronic kidney disease stage 5 according to whether they chose renal replacement therapy or conservative management. DESIGN: Retrospective observational study. SETTING/PARTICIPANTS: Patients aged over 70 years attending pre-dialysis clinic. RESULTS: In total, 172 patients chose conservative management and 269 chose renal replacement therapy. The renal replacement therapy group survived for longer when survival was taken from the time estimated glomerular filtration rate <20 mL/min (p < 0.0001), <15 mL/min (p < 0.0001) and <12 mL/min (p = 0.002). When factors influencing survival were stratified for both groups independently, renal replacement therapy failed to show a survival advantage over conservative management, in patients older than 80 years or with a World Health Organization performance score of 3 or more. There was also a significant reduction in the effect of renal replacement therapy on survival in patients with high Charlson's Comorbidity Index scores. The relative risk of an acute hospital admission (renal replacement therapy vs conservative management) was 1.6 (p < 0.05; 95% confidence interval = 1.14-2.13). A total of 47% of conservative management patients died in hospital, compared to 69% undergoing renal replacement therapy (Renal Registry data). Seventy-six percent of the conservative management group accessed community palliative care services compared to 0% of renal replacement therapy patients. CONCLUSIONS: For patients aged over 80 years, with a poor performance status or high co-morbidity scores, the survival advantage of renal replacement therapy over conservative management was lost at all levels of disease severity. Those accessing a conservative management pathway had greater access to palliative care services and were less likely to be admitted to or die in hospital.

Supportive and palliative care for people with end-stage renal disease.

Advanced renal failure has a mortality rate worse than for most cancers with significant symptom burden. Despite this palliative care for this group has been poor. This article summarizes the role that palliative and nephrology teams can play in optimizing end-of-life care.