PT  - JOURNAL ARTICLE
AU  - Inger van Heijl
AU  - Valentijn A. Schweitzer
AU  - C.H. Edwin Boel
AU  - Jan Jelrik Oosterheert
AU  - Susanne M. Huijts
AU  - Wendelien Dorigo-Zetsma
AU  - Paul D. van der Linden
AU  - Marc J.M. Bonten
AU  - Cornelis H. van Werkhoven
TI  - Confounding by indication of the safety of de-escalation in community-acquired pneumonia: a simulation study embedded in a prospective cohort
AID  - 10.1101/652610
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 652610
4099  - http://biorxiv.org/content/early/2019/05/28/652610.short
4100  - http://biorxiv.org/content/early/2019/05/28/652610.full
AB  - Background 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.Methods 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.Results 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. The adjusted hazard ratio of de-escalation for 30-day mortality (compared to patients with unchanged coverage), without adjustment for clinical stability, was 0.36 (95%CI: 0.18-0.73). If 90% to 100% of de-escalated patients were clinically stable on day three, the fully adjusted hazard ratio would be 0.53 (95%CI: 0.26-1.08) to 0.90 (95%CI: 0.42-1.91), respectively. The simulated confounder was substantially stronger than any of the baseline confounders in our dataset.Conclusions With plausible, literature-based assumptions, clinical stability is a very strong confounder for the effects of de-escalation. Quantification of effects of de-escalation on patient outcomes without proper adjustment for clinical stability results in strong negative bias. As a result, the safety of de-escalation remains to be determined.