Heterogeneity of treatment effect by baseline risk of mortality in critically ill patients: re-analysis of three recent sepsis and ARDS randomised controlled trials

• Published in: Critical care (London, England) England), 2019-05, Vol.23 (1), p.156-156, Article 156
• Main Authors: Santhakumaran, Shalini, Gordon, Anthony, Prevost, A Toby, O'Kane, Cecilia, McAuley, Daniel F, Shankar-Hari, Manu
• Format: Article
• Language: English
• Subjects: Adult; Adult respiratory distress syndrome; Aged; Anti-Inflammatory Agents - therapeutic use; APACHE; Cardiotonic Agents - therapeutic use; Care and treatment; Clinical trials; Critical care; Critical Illness - mortality; Critical Illness - therapy; Critically ill persons; Death; Evaluation; Evidence-based medicine; Female; Glucocorticoids; Guideline Adherence - trends; Health; Hospital Mortality - trends; Humans; Hydrocortisone; Hydrocortisone - therapeutic use; Hydroxymethylglutaryl-CoA Reductase Inhibitors - therapeutic use; Infection; Intensive Care Units - organization & administration; Intensive Care Units - statistics & numerical data; Intervention; Male; Middle Aged; Models, statistical; Mortality; Patient outcomes; Patients; Physiological aspects; Physiology; Randomisation; Randomized Controlled Trials as Topic; Respiratory distress syndrome; Respiratory Distress Syndrome - drug therapy; Respiratory Distress Syndrome - mortality; Risk; Sepsis; Sepsis - drug therapy; Sepsis - mortality; Sepsis, acute respiratory distress syndrome; Simendan - therapeutic use; Simvastatin; Simvastatin - therapeutic use; Study design; Treatment Outcome; Vasoconstrictor Agents - therapeutic use; Vasopressins - therapeutic use
• ISSN: 1364-8535; 1466-609X; 1364-8535; 1366-609X
• DOI: 10.1186/s13054-019-2446-1

Randomised controlled trials (RCTs) enrolling patients with sepsis or acute respiratory distress syndrome (ARDS) generate heterogeneous trial populations. Non-random variation in the treatment effect of an intervention due to differences in the baseline risk of death between patients in a population represents one form of heterogeneity of treatment effect (HTE). We assessed whether HTE in two sepsis and one ARDS RCTs could explain indeterminate trial results and inform future trial design. We assessed HTE for vasopressin, hydrocortisone and levosimendan in sepsis and simvastatin in ARDS patients, on 28-day mortality, using the total Acute Physiology And Chronic Health Evaluation II (APACHE II) score as the baseline risk measurement, comparing above (high) and below (low) the median score. Secondary risk measures were the acute physiology component of APACHE II and predicted risk of mortality using the APACHE II score. HTE was quantified both in additive (difference in risk difference (RD)) and multiplicative (ratio of relative risks (RR)) scales using estimated treatment differences from a logistic regression model with treatment risk as the interaction term. The ratio of the odds of death in the highest APACHE II quartile was 4.9 to 7.4 times compared to the lowest quartile, across the three trials. We did not observe HTE for vasopressin, hydrocortisone and levosimendan in the two sepsis trials. In the HARP-2 trial, simvastatin reduced mortality in the low APACHE II group and increased mortality in the high APACHE II group (difference in RD = 0.34 (0.12, 0.55) (p = 0.02); ratio of RR 3.57 (1.77, 7.17) (p