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Randomized Controlled Trial
. 2024 Apr;165(4):785-799.
doi: 10.1016/j.chest.2023.11.019. Epub 2023 Nov 17.

Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life

Yonatan Y Greenstein  1 , Kinsley Hubel  2 , Joshua Froess  3 , Stephen R Wisniewski  3 , Vidya Venugopal  3 , Yu-Hsuan Lai  3 , Jeff S Berger  4 , Steven Y Chang  5 , Christos Colovos  6 , Faraaz Shah  7 , Lucy Z Kornblith  8 , Patrick R Lawler  9 , Manila Gaddh  10 , Raquel Morillo Guerrero  11 , William Nkemdirim  12 , Renato D Lopes  13 , Harmony R Reynolds  4 , Jose Seijas Amigo  14 , Lana Wahid  13 , Ajani Zahra  15 , Ewan C Goligher  16 , Ryan Zarychanski  17 , Eric Leifer  18 , David T Huang  7 , Matthew D Neal  7 , Judith S Hochman  4 , Mary Cushman  6 , Michelle N Gong  19
Affiliations
Randomized Controlled Trial

Symptoms and Impaired Quality of Life After COVID-19 Hospitalization: Effect of Therapeutic Heparin in Non-ICU Patients in the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 Acute Trial: Effect on 3-Month Symptoms and Quality of Life

Yonatan Y Greenstein et al. Chest. 2024 Apr.

Abstract

Background: Therapeutic-dose heparin decreased days requiring organ support in noncritically ill patients hospitalized for COVID-19, but its impact on persistent symptoms or quality of life (QOL) is unclear.

Research question: In the Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE (ACTIV-4a) trial, was randomization of patients hospitalized for COVID-19 illness to therapeutic-dose vs prophylactic heparin associated with fewer symptoms and better QOL at 90 days?

Study design and methods: This was an open-label randomized controlled trial at 34 hospitals in the United States and Spain. A total of 727 noncritically ill patients hospitalized for COVID-19 from September 2020 to June 2021 were randomized to therapeutic-dose vs prophylactic heparin. Only patients with 90-day data on symptoms and QOL were analyzed. We ascertained symptoms and QOL by the EQ-5D-5L at 90-day follow-up in a preplanned analysis for the ACTIV-4a trial. Individual domains assessed by the EQ-5D-5L included mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Univariate and multivariate analyses were performed.

Results: Among 571 patients, 288 (50.4%) reported at least one symptom. Among 410 patients, 148 (36.1%) reported moderate to severe impairment in one or more domains of the EQ-5D-5L. The presence of 90-day symptoms was associated with moderate-severe impairment in the EQ-5D-5L domains of mobility (adjusted OR [aOR], 2.37; 95% CI, 1.22-4.59), usual activities (aOR, 3.66; 95% CI, 1.75-7.65), pain (aOR, 2.43; 95% CI, 1.43-4.12), and anxiety (aOR, 4.32; 95% CI, 2.06-9.02), compared with patients reporting no symptoms There were no differences in symptoms or in the overall EQ-5D-5L index score between treatment groups. Therapeutic-dose heparin was associated with less moderate-severe impairment in all physical functioning domains (mobility, self-care, usual activities) but was independently significant only in the self-care domain (aOR, 0.32; 95% CI, 0.11-0.96).

Interpretation: In a randomized controlled trial of hospitalized noncritically ill patients with COVID-19, therapeutic-dose heparin was associated with less severe impairment in the self-care domain of EQ-5D-5L. However, this type of impairment was uncommon, affecting 23 individuals.

Clinical trial registration: ClinicalTrials.gov; No.: NCT04505774; URL: www.

Clinicaltrials: gov.

Keywords: COVID-19; anticoagulation; heparin; quality of life.

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Conflict of interest statement

Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: Y. Y. G. is the founder and CEO of Sabra Medical, Inc outside the submitted work. J. S. B. received grants from the National Heart, Lung, and Blood Institute and American Heart Association and personal fees from Jannssen and Amgen, outside the submitted work. L. Z. K. received consulting fees from Cerus, Gamma Diagnostics, and University of Maryland, outside the submitted work. P. R. L. received grants from the National Institutes of Health during the conduct of the study. R. D. L. receive consulting fees from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Medtronic, Merck, Pfizer, Portola, and Sanofi and grants from Bristol-Myers Squibb, GlaxoSmithKline, Medtronic, Pfizer, and Sanofi, outside the submitted work. H. R. R. received nonfinancial support from Siemens, Philips, and Abbott Vascular and grants from the National Heart, Lung, and Blood Institute, outside the submitted work. M. D. N. received personal fees from Haemonetics and Takeda, grants from Instrumentation Laboratories and Haemonetics, and serves on the advisory board for and has equity stake in Haima Therapeutics, outside the submitted work. M. N. G. received grants from the National Institutes of Health and the Centers for Disease Control and Prevention, outside the submitted work. None declared (K. H., J. F., S. R. W., V. V., Y. L., S. Y. C., C. C., F. S., M. G., R. M. G., W. N., J. S. A., L. W., A. Z., E. C. G., R. Z., E. L., D. T. H., J. S. H., M. C.).

Figures

None
Graphical abstract
Figure 1
Figure 1
Enrollment and inclusion in analysis. Patients from the ACTIV-4a clinical trial were identified for this analysis. Only noncritically ill patients alive at 90 days with symptom data (571) were included in the analysis. ACTIV-4a = Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE. MR = mortality rate; PROTECT = Prophylaxis for Thromboembolism in Critical Care Trial.
Figure 2
Figure 2
A-C, Patient-reported symptoms and moderate to severe impairment in EQ-5D-5L at 90 days. A, The proportion of patients reporting any symptoms at 90 days after enrollment. Respiratory symptoms∗ were the most commonly reported. B, Proportion of patients by symptom burden score† at 90 days after enrollment with 23.4% of patients reporting at least one symptom at 90 days. C, Proportion of patients reporting at least moderate impairment in the EQ-5D-5L domains at 90 days. ∗Respiratory symptoms are a composite of cough, dyspnea with exertion, and dyspnea at rest. †Symptom burden score was defined as the total number of the following symptoms: cough, dyspnea with exertion, dyspnea at rest, chest pain or tightness, feeling tired or lack of energy, and cognitive impairment.
Figure 3
Figure 3
Adjusted ORs of moderate-severe impairment in EQ-5D-5L domains by treatment assignment in the ACTIV-4a moderate cohort. In the domain of self-care there was a significant reduction in the degree of impairment reported in patients who received therapeutic-dose heparin. There was a trend in both mobility and usual activity to reduced impairment in patients who received therapeutic-dose heparin. Logistic regressions were adjusted for, using age, sex, residence before admission, and malignancy. ACTIV-4a = Accelerating COVID-19 Therapeutic Interventions and Vaccines 4 ACUTE; aOR = adjusted OR.
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