Confounding by indication of the safety of de-escalation in community-acquired pneumonia: A simulation study embedded in a prospective cohort

• Published in: PloS one 2019-09, Vol.14 (9), p.e0218062-e0218062
• Main Authors: van Heijl, Inger, Schweitzer, Valentijn A, Boel, C H Edwin, Oosterheert, Jan Jelrik, Huijts, Susanne M, Dorigo-Zetsma, Wendelien, van der Linden, Paul D, Bonten, Marc J M, van Werkhoven, Cornelis H
• Format: Article
• Language: English
• Subjects: Aged; Aged, 80 and over; Analysis; Anti-Bacterial Agents - pharmacology; Anti-Bacterial Agents - therapeutic use; Antibiotics; Bias; Biology and Life Sciences; Care and treatment; Chemotherapy; Clinical outcomes; Clinical trials; Community-Acquired Infections - drug therapy; Community-Acquired Infections - epidemiology; Community-Acquired Infections - microbiology; Comorbidity; Confounding Factors, Epidemiologic; Data acquisition; Dependent variables; Drug stores; Epidemiology; Female; Genetic aspects; Hazards; Health hazards; Health sciences; Hospitals; Humans; Immunization; Indication; Infectious diseases; Intensive care; Male; Medical research; Medicine and Health Sciences; Middle Aged; Mortality; Observational studies; Patients; Pharmacy; Physical Sciences; Pneumonia; Pneumonia - drug therapy; Pneumonia - epidemiology; Pneumonia - microbiology; Population; Primary care; Public Health Surveillance; Regression analysis; Research and Analysis Methods; Risk factors; Simulation; Stability; Studies; Systematic review; Tetracyclines; Time dependence; Treatment Outcome
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0218062

Observational studies have demonstrated that de-escalation of antimicrobial therapy is independently associated with lower mortality. This most probably results from confounding by indication. Reaching clinical stability is associated with the decision to de-escalate and with survival. However, studies rarely adjust for this confounder. We quantified the potential confounding effect of clinical stability on the estimated impact of de-escalation on mortality in patients with community-acquired pneumonia. Data were used from the Community-Acquired Pneumonia immunization Trial in Adults (CAPiTA). The primary outcome was 30-day mortality. We performed Cox proportional-hazards regression with de-escalation as time-dependent variable and adjusted for baseline characteristics using propensity scores. The potential impact of unmeasured confounding was quantified through simulating a variable representing clinical stability on day three, using data on prevalence and associations with mortality from the literature. Of 1,536 included patients, 257 (16.7%) were de-escalated, 123 (8.0%) were escalated and in 1156 (75.3%) the antibiotic spectrum remained unchanged. Crude 30-day mortality was 3.5% (9/257) and 10.9% (107/986) in the de-escalation and continuation groups, respectively. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.39 (95%CI: 0.19-0.79). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.56 (95%CI: 0.27-1.12) to 1.04 (95%CI: 0.49-2.23), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. This study suggests the effect of de-escalation on mortality needs further well-designed prospective research to determine effect size more accurately.