Objectives: To assess the external validity of a pragmatic, investigator-initiated RCT on treatment of severe infections caused by methicillin-resistant Staphylococcus aureus (MRSA), we compared patient characteristics and treatment effect estimates for patients included in the RCT versus those excluded.
Participants and outcomes: The RCT included hospitalised patients with documented or highly-probable invasive MRSA infections who were randomised to vancomycin versus trimethoprim-sulfamethoxazole (TMP-SMX) treatment, between 2007 and 2014. A concomitant observational study prospectively included all consecutive patients, between 2008 and 2011, who were excluded from the RCT due to no consent, meningitis, left-sided endocarditis, severe neutropaenia, chronic renal dialysis or treatment with study medications for longer than 48 h. The primary outcomes were clinical failure at day 7 and 30-day mortality for both studies. We compared baseline and infection characteristics, outcome rates and treatment effect estimates for included versus excluded patients.
Results: The RCT included 252 patients who were compared with 220 excluded patients who were observed. Inability to provide informed consent was the main reason for patient exclusion. Excluded patients' functional and cognitive performance was significantly poorer than that of included patients. Sepsis was more severe among excluded patients (higher rates of mechanical ventilation, indwelling catheters, septic shock and organ failure). Clinical failure occurred in 83/252 (32.9%) versus 175/220 (79.5%) and deaths in 32 (12.7%) versus 64 (29.1%) for included versus excluded patients, p<0.001 for both comparisons. Comparing vancomycin to TMP-SMX, in the RCT mortality, was non-significantly lower with vancomycin (OR 0.76, 95% CIs 0.36 to 1.62), while in the observational analysis of excluded patients, mortality was significantly higher with vancomycin (OR 2.63, 1.04 to 6.65), p=0.04 for the difference.
Conclusions: Patient characteristics, outcome event rates and treatment effects differed significantly in the setting of a RCT, despite its pragmatic design, compared to patients treated outside the trial settings.
Keywords: INFECTIOUS DISEASES; MEDICAL ETHICS; STATISTICS & RESEARCH METHODS.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.