Clinical trial NCT05509647: Unfractionated Heparin in COVID-19 and Non-COVID-19 Patients
Official title: Unfractionated Heparin in COVID-19 and Non-COVID-19 Patients - an Observational Study.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Heparin Overdose of Undetermined Intent
COVID-19
Lead sponsor: Leiden University Medical Center
Sponsor class: OTHER
First posted: 2022-08-22
Enrollment: 1500
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: RETROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: Patients admitted to the ICU in the above mentioned periods of time and in need for unfractionated heparin treatment are eligible to participate in the study. There is no selection bias: all patients fulfilling the entry criteria will be included.

Brief summary: The majority of ICU patients with COVID-19 show profound activation of coagulation, potentially resulting in thromboembolic events. In the treatment of these thromboembolic events it seemed that very high dosages of unfractionated heparin were necessary to achieve therapeutic values of aPTT and anti-Xa levels. The aim of this study is to explore whether heparin dosages are higher in COVID-19 patients compared to non-COVID-19 patients, to determine the correlation between aPTT and anti-Xa values and to explore possible causes for non-correlating aPTT and anti-Xa, including CRP and AT plasma levels.

Detailed description: CoVID-19 is a viral disease caused by SARS-CoV-2 virus that may affect many organ systems. Patients with severe disease almost invariably have profound pulmonary inflammation and may require mechanical ventilation and prolonged ICU admission. Mortality in ICU patients may be up to 50%. In the majority of patients with CoVID-19 in the ICU, profound activation of coagulation is present as reflected by d-dimer levels up to 20.000 mg/L or higher. Patients with proven pulmonary thrombosis are commonly treated with unfractionated heparin (UFH). Typically, it seemed that very high dosages of UFH were necessary to achieve therapeutic values of aPTT and anti-Xa levels in COVID-19 patients. Though, the question remains whether dosages given in COVID-19 patients were indeed extravagant compared to non-COVID-19 patients and what potential causes of these high dosages might be. Earlier research already implied that APTT, which is a primarily used parameter to dose UFH, is not accurate and rather anti-Xa levels should be used. Other potential reasons for the high doses are that COVID-19 patients show signs of heparin resistance, possible due to high inflammation parameters. As overdosing of heparin can lead to serious bleeding complications, more understanding on heparin dosage, e.g. parameters to rely on and potential influencing factors, in COVID-19 patients is needed. The primary objective of this study is to determine whether heparin dosages are higher in COVID-19 patients compared to non COVID-19 patients. The secondary objective is to determine the correlation between aPTT and anti-Xa values and to explore possible causes for non-correlating aPTT and anti-Xa, including CRP and AT plasma levels.

Eligibility criteria: Inclusion Criteria Covid-19 group:

* Covid-19 disease proven by PCR of nose- or airway sample
* Age ≥ 18 years
* Admitted to the ICU from the 15th of March 2020 until 1st of January 2022
* Treated with unfractionated heparin aiming at aPTT 60-80 sec and/or anti-Xa level 0.3-0.7 iE/ml

Inclusion Criteria non-Covid-19 group:

* Age ≥ 18 years
* Admitted to the ICU between the 1st of January 2014 and 1st of January 2020
* Treated with unfractionated heparin aiming at aPTT 60-80 sec and/or anti-Xa level 0.3-0.7 iE/ml

Exclusion Criteria:

- Treatment with anticoagulants other than UFH or fibrinolytics

Primary outcomes:
measure: Heparin dosage
timeFrame: Until end of heparin therapy or ICU discharge, whatever comes first.
Secondary outcomes:
measure: Correlation between aPTT and anti-Xa values
timeFrame: Until end of heparin therapy or ICU discharge, whatever comes first.
measure: Correlation between non-correlating aPTT and Anti-Xa levels and CRP
timeFrame: Until end of heparin therapy or ICU discharge, whatever comes first.
measure: Correlation between non-correlating aPTT and Anti-Xa levels and AT plasma levels
timeFrame: Until end of heparin therapy or ICU discharge, whatever comes first.
Other outcomes:
Locations:
city: Leiden
country: Netherlands
facility: Leiden University Medical Centre
state: Zuid-holland
Study officials:
affiliation: Leiden University Medical Centre
name: Evert de Jonge, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Yang X, Yu Y, Xu J, Shu H, Xia J, Liu H, Wu Y, Zhang L, Yu Z, Fang M, Yu T, Wang Y, Pan S, Zou X, Yuan S, Shang Y. Clinical course and outcomes of critically ill patients with SARS-CoV-2 pneumonia in Wuhan, China: a single-centered, retrospective, observational study. Lancet Respir Med. 2020 May;8(5):475-481. doi: 10.1016/S2213-2600(20)30079-5. Epub 2020 Feb 24.
citation: Thachil J, Tang N, Gando S, Falanga A, Levi M, Clark C, Iba T, Cattaneo M. Type and dose of heparin in Covid-19: Reply. J Thromb Haemost. 2020 Aug;18(8):2063-2064. doi: 10.1111/jth.14870. Epub 2020 May 11. No abstract available.
citation: Arachchillage DRJ, Kamani F, Deplano S, Banya W, Laffan M. Should we abandon the APTT for monitoring unfractionated heparin? Thromb Res. 2017 Sep;157:157-161. doi: 10.1016/j.thromres.2017.07.006. Epub 2017 Jul 6.
citation: White D, MacDonald S, Bull T, Hayman M, de Monteverde-Robb R, Sapsford D, Lavinio A, Varley J, Johnston A, Besser M, Thomas W. Heparin resistance in COVID-19 patients in the intensive care unit. J Thromb Thrombolysis. 2020 Aug;50(2):287-291. doi: 10.1007/s11239-020-02145-0.