Effect of therapeutic-dose heparin on severe acute kidney injury and death in noncritically ill patients hospitalized for COVID-19: a prespecified secondary analysis of the ACTIV4a and ATTACC randomized trial

Nathaniel R Smilowitz; Erinn M Hade; Lucy Z Kornblith; Lana A Castellucci; Mary Cushman; Michael Farkouh; Michelle N Gong; Anna Heath; Beverly J Hunt; Keri S Kim; Andrei Kindzelski; Patrick Lawler; David E Leaf; Ewan Goligher; Eric S Leifer; Bryan J McVerry; Harmony R Reynolds; Ryan Zarychanski; Judith S Hochman; Matthew D Neal; Jeffrey S Berger

doi:10.1016/j.rpth.2023.102167

Effect of therapeutic-dose heparin on severe acute kidney injury and death in noncritically ill patients hospitalized for COVID-19: a prespecified secondary analysis of the ACTIV4a and ATTACC randomized trial

Res Pract Thromb Haemost. 2023 Aug 9;7(6):102167. doi: 10.1016/j.rpth.2023.102167. eCollection 2023 Aug.

Authors

Nathaniel R Smilowitz¹, Erinn M Hade¹, Lucy Z Kornblith², Lana A Castellucci^{3

4}, Mary Cushman⁵, Michael Farkouh^{6

7}, Michelle N Gong^{8

9}, Anna Heath¹⁰, Beverly J Hunt¹¹, Keri S Kim¹², Andrei Kindzelski¹³, Patrick Lawler^{6

7}, David E Leaf¹⁴, Ewan Goligher^{7

15}, Eric S Leifer¹³, Bryan J McVerry^{16

17}, Harmony R Reynolds¹, Ryan Zarychanski^{18

19}, Judith S Hochman¹, Matthew D Neal^{16

17}, Jeffrey S Berger¹

Affiliations

¹ NYU Grossman School of Medicine, New York, New York, USA.
² Zuckerberg San Francisco General Hospital, University of California, San Francisco, California, USA.
³ Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.
⁴ University of Ottawa, Ottawa, Ontario, Canada.
⁵ Larner College of Medicine at the University of Vermont, Burlington, Vermont, USA.
⁶ Peter Munk Cardiac Centre at University Health Network, Toronto, Ontario, Canada.
⁷ University of Toronto, Toronto, Ontario, Canada.
⁸ Montefiore Medical Center, Bronx, New York, USA.
⁹ Albert Einstein College of Medicine, Bronx, New York, USA.
¹⁰ The Hospital for Sick Children, Toronto, Ontario, Canada.
¹¹ Kings College, London, UK.
¹² University of Illinois, Chicago, Illinois, USA.
¹³ National Heart Lung & Blood Institute, NIH, Bethesda, Maryland, USA.
¹⁴ Brigham and Women's Hospital Harvard Medical School, Boston, Massachusetts, USA.
¹⁵ University Health Network, Toronto, Ontario, Canada.
¹⁶ University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
¹⁷ UPMC, Pittsburgh, Pennsylvania, USA.
¹⁸ University of Manitoba, Winnipeg, Manitoba, Canada.
¹⁹ CancerCare Manitoba, Winnipeg, Manitoba, Canada.

Abstract

Background: Acute kidney injury (AKI) in patients with COVID-19 is partly mediated by thromboinflammation. In noncritically ill patients with COVID-19, therapeutic-dose anticoagulation with heparin increased the probability of survival to hospital discharge with reduced use of cardiovascular or respiratory organ support.

Objectives: We investigated whether therapeutic-dose heparin reduces the incidence of AKI or death in noncritically ill patients hospitalized for COVID-19.

Methods: We report a prespecified secondary analysis of the ACTIV4a and ATTACC open-label, multiplatform randomized trial of therapeutic-dose heparin vs usual-care pharmacologic thromboprophylaxis on the incidence of severe AKI (≥2-fold increase in serum creatinine or initiation of kidney replacement therapy (KDIGO stage 2 or 3) or all-cause mortality in noncritically ill patients hospitalized for COVID-19. Bayesian statistical models were adjusted for age, sex, D-dimer, enrollment period, country, site, and platform.

Results: Among 1922 enrolled, 23 were excluded due to pre-existing end stage kidney disease and 205 were missing baseline or follow-up creatinine measurements. Severe AKI or death occurred in 4.4% participants assigned to therapeutic-dose heparin and 5.5% assigned to thromboprophylaxis (adjusted relative risk [aRR]: 0.72; 95% credible interval (CrI): 0.47, 1.10); the posterior probability of superiority for therapeutic-dose heparin (relative risk < 1.0) was 93.6%. Therapeutic-dose heparin was associated with a 97.7% probability of superiority to reduce the composite of stage 3 AKI or death (3.1% vs 4.6%; aRR: 0.64; 95% CrI: 0.40, 0.99) compared to thromboprophylaxis.

Conclusion: Therapeutic-dose heparin was associated with a high probability of superiority to reduce the incidence of in-hospital severe AKI or death in patients hospitalized for COVID-19.

Keywords: COVID-19; acute kidney injury; anticoagulants; death; heparin; kidney diseases; mortality.