Discussion
pleural infections, pleural infection, pain
PLEURAL INFECTION, ADVERSE EVENTS, ADVERSE EVENT, SECONDARY, STRUCK
The treatment paradigm in pleural infection is based on expert consensus and has remained largely unchanged in the past two decades. The addition of combination intrapleural fibrinolytic and enzyme therapy has been a major advance. However, modern surgical techniques have meant that VATS has become a more accessible treatment for a significantly larger proportion of patients. Despite these developments, the two treatments have not been compared in a prospective multicenter study, resulting in variability in clinical practice and guideline recommendations (In this study, the first head-to-head randomized study of IET versus surgery early in treatment, we demonstrated that patients presenting with pleural infection are amenable to early escalation to more “aggressive” therapies. After an initial period of standard care (chest tube drainage and antibiotics), using a protocolized definition of treatment failure, and despite a concurrent COVID-19 pandemic, 62% of eligible patients were successfully randomized to receive early IET or early surgical evaluation. Of the eligible patients who were not randomized, only 23% were not randomized as a result of direct participant refusal; hence, in general, there is equipoise and acceptance among clinicians and patients about participation in a surgery-versus-nonsurgery trial in pleural infection.Although early cross-over (<48 h after randomization) was permissible if deemed clinically necessary, the high proportion of early cross-over in participants randomized to receive standard care likely represents a general trend toward early escalation among clinicians, suggesting that “standard care” has evolved ahead of guideline-driven practice. The degree of cross-over provides credence to the exclusion of a standard care arm in future trials in lieu of head-to-head randomization to IET and surgery alone. Furthermore, the observation that these patients were not heavily skewed toward one intervention (four received surgery, seven received IET) suggests reasonable equipoise among clinicians. The run-in period of initial treatment with antibiotics and a chest tube remains justified to exclude quick responders who may not require further intervention, who comprised approximately 13% of participants in the present study. This is an important finding and will inform future sample size calculations in a definitive trial.In terms of the “active” interventions, treatment compliance was notably lower in the surgical arm (50%) compared with the IET arm (79%). The most common reason for patients not undergoing surgery was the risk/benefit balance of VATS no longer being in favor of proceeding with surgery by the time an operation was feasible. This should be considered when planning future phase III studies in which there is a large difference in delivering the trial intervention between two arms. Nonetheless, although most eligible patients agreed to be randomly allocated to surgery, and that anesthesia risk precluded only a minority of participants from this allocation, a minimum fitness criterion may potentially optimize compliance in a future phase III study while maintaining the strength of MIST-3 in avoiding the selection bias of previous surgical RCTs (Adverse events related to treatment arm were minimal throughout the study (overall adverse events, 4 of 60; 6.7%). The most common AE was pain in the IET arm, which is well documented (A notable finding among the secondary outcomes concerned LOS. Despite median time to intervention varying significantly between IET and VATS (1 d vs. 3.5 d), it is of added value that these were similar in a recent U.S. pilot single-center RCT (Patient-reported outcome measures were a key focus in this study, as these have not been specifically evaluated in pleural infection. The HADS is a simple and effective measure of psychological and emotional distress (The impact of the COVID-19 pandemic on the MIST-3 trial cannot be understated. The trial was recruiting well ahead of target until March 2020, when the first wave of the pandemic struck U.K. hospitals. Hospitalizations became predominantly COVID-19–related, and a substantial reduction in non–COVID-19–related admissions was observed across the Western world (To our knowledge, MIST-3 is the first prospective multicenter study to successfully randomly assign patients with pleural infections to receive IET versus surgery. The results provide evidence for feasibility and acceptability, but, arguably, the study’s main success has been in identifying key aspects of study design and methodology that will inform future protocols for a trial of this kind. Strengths of the study include clear and standardized pleural infection diagnostic criteria and protocolized definition of medical treatment failure before randomization. Although the study is small and not powered to detect any treatment differences between groups, early intervention in general appeared to show a significant benefit in terms of LOS compared with standard care, and this finding adds credence to the need for a larger definitive study. Despite ITT analysis being the gold standard because it provides an unbiased estimate of treatment effect, its interpretation becomes difficult when a significant proportion of participants do not receive the intervention as randomized, as occurred in the surgical arm. We fully accept that a much larger study with longer follow-up would be needed to provide reliable evidence in regard to mortality, quality of life improvement, and long-term survival between IET and surgery. Based on the results of the MIST-3 study, a further definitive phase III study is being developed that does not include a standard care arm.