Durable functional limitation in patients with coronavirus disease-2019 admitted to intensive care and the effect of intermediate-dose vs standard-dose anticoagulation on functional outcomes

Abstract

Introduction: Patients affected with severe forms of coronavirus disease 2019 (COVID-19) suffer from a wide range of sequelae, from limited airway diseases to multiple organ failure. These sequelae may create exercise limitation, impair the daily activity and thus impact the mental health and the social life. However, the extent of functional limitations and depressive symptoms are understudied especially in patients with COVID-19 after intensive care unit (ICU) hospitalization.

Methods: The Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) was a clinical trial that randomized ICU patients with COVID-19 to intermediate-dose vs standard-dose anticoagulation. In the current study, we assessed the interval change in 30-day and 90-day functional limitations based on the post-COVID-19 functional status scale (PCFS) and depressive symptoms based on the Patient Health Questionnaire-2 (PHQ-2) in the trial participants. We also assessed the effect of intermediate-dose vs standard-dose prophylactic anticoagulation on the functional outcomes and depressive symptoms.

Results: Of 600 randomized patients in INSPIRATION, 375 (age: 62 years; 42% women) participated in the functional status study. 195 patients died during the 90-day follow up (191 by day 30). Among survivors, between day 30 and day 90, the proportion of patients with moderate-to-severe functional limitation (PCSF grade 3-or-4) decreased from 20.0% to 4.8% (P <0.001) and PHQ-2 ≥ 3 decreased from 25.5% to 16.6% (P = 0.05). The proportion of patients with no functional limitations (PCFS grade 0) increased (4.2% to 15.4%, P<0.001). Intermediate-dose compared with standard-dose prophylactic anticoagulation did not impact the 90-day proportion of patients with PCFS grade 3-or-4 (5.3% vs 4.2%; odds ratio (OR), 1.20, [95% CI, 0.46-3.11]; P = 0.80) or PHQ-2 ≥ 3 (17.9% vs 15.3%; OR, 1.14, [95% CI, 0.79-1.65]; P = 0.14), with similar results when accounting for study center.

Conclusion: In patients with COVID-19 admitted to the ICU, functional limitations and depressive symptoms were common at 30-day follow-up and had some improvement by 90-day follow-up among survivors. Intermediate-dose compared to standard-dose prophylactic anticoagulation did not improve functional outcomes.

Keywords: Anticoagulation; COVID-19; Patient health questionnaire-2; The post-COVID-19 functional status scale.

Fig. 1

Schematic representation of patient inclusion in INSPIRATION functional status(FS) cohort. *Since death is one of the pre-defined categories for PCFS, patients who died during follow-up were being considered for functional status analyses. However, for depression screening, patients needed to be alive to complete the questionnaire.

Fig. 2

PCFS and PHQ-2 changes in 1-and 3-month follow up. Panel A. Perceived change in PCFS at 1- and 3-month intervals (Sankey plot). Notably, only four patients (all categorized by PCFS grade 4 at Day 30) died between days 31 and 90. The proportion of patients with severe functional limitation decreased over time. The proportion of patients with severe functional limitation (PCFS grade 3-or-4) decreased by 3-month follow-up. Panel B, the proportion of patients with PHQ-2 ≥ 3 decreased over time. PCFS denotes for Post-COVID-19 functional scale, PHQ-2, Patient Health Questionnaire-2.

Fig. 3

Three-month PCFS Grading (Panel A) and proportion of patients PHQ-2 ≥ 3 (Panel B) between the two anticoagulation regimens (Intermediate-dose versus standard-dose prophylactic anticoagulation). PCFS grading classified patients from 0 (no functional limitations) to 4 (severe functional limitations) and 5 (death). PHQ-2 ≥ 3 shows higher odds of major depressive disorder. PCFS denotes for Post-COVID-19 functional scale, PHQ-2, Patient Health Questionnaire-2.