Assessing differential application of thromboprophylaxis regimes related to risk of pulmonary embolism and mortality in COVID-19 patients through instrumental variable analysis
Thrombotic complications are common in Coronavirus disease 2019 (COVID-19) patients, with pulmonary embolism (PE) being the most frequent. Randomised trials have provided inconclusive results on the optimal dosage of thromboprophylaxis in critically ill COVID-19 patients. We utilized data from the multicentre CAPACITY-COVID patient registry to assess the effect of differential application of Low Molecular Weight Heparin (LMWH) dose protocols on PE and in-hospital mortality risk in critically ill COVID-19 patients. An instrumental variable analysis was performed to estimate the intention-to-treat effect, utilizing differences in thromboprophylaxis prescribing behaviour between hospitals. We included 939 patients with PCR confirmed SARS-CoV-2 infection from 34 hospitals. Two-hundred-and-one patients (21%) developed a PE. The adjusted cause-specific HR of PE was 0.92 (95% CI: 0.73-1.16) per doubling of LMWH dose. The adjusted cause-specific HR for in-hospital mortality was 0.82 (95% CI: 0.65-1.02) per doubling of LMWH dose. This dose-response relationship was shown to be non-linear. To conclude, this study did not find evidence for an effect of LMWH dose on the risk of PE, but suggested a non-linear decreased risk of in-hospital mortality for higher doses of LMWH. However, uncertainty remains, and the dose-response relationship between LMWH dose and in-hospital mortality needs further investigation in well-designed studies.
Authors
- Saskia Middeldorp (ORCID: https://orcid.org/0000-0002-1006-6420)
- Hans‐Marc J. Siebelink
- Michiel Coppens (ORCID: https://orcid.org/0000-0001-6891-9062)
- Frank W.G. Leebeek (ORCID: https://orcid.org/0000-0001-5677-1371)
- Evert de Jonge (ORCID: https://orcid.org/0000-0003-1431-8039)
- Koen S. Simons (ORCID: https://orcid.org/0000-0001-8120-5566)
- Wiek H. van Gilst (ORCID: https://orcid.org/0000-0003-2968-8585)
- Y.L. Soei
- Linda Nab (ORCID: https://orcid.org/0000-0002-1821-7246)
- R. A. Tio
- Marthe S. Paats (ORCID: https://orcid.org/0000-0003-1602-6195)
- Gaby Captur
- Matthijs C. Brouwer (ORCID: https://orcid.org/0000-0001-7775-7843)
- Thomas Langerak (ORCID: https://orcid.org/0000-0003-4340-1560)
- Eric Wierda (ORCID: https://orcid.org/0000-0002-9998-5035)
- Josep Redón (ORCID: https://orcid.org/0000-0001-8777-6773)
- Fleur H.J. Kaptein (ORCID: https://orcid.org/0000-0003-2274-4820)
- Marion Koopmans (ORCID: https://orcid.org/0000-0002-5204-2312)
- Johannes G. Krabbe (ORCID: https://orcid.org/0000-0003-1585-9304)
- Sabrina H. van Ierssel (ORCID: https://orcid.org/0000-0003-2955-4130)
- Willem M. Lijfering (ORCID: https://orcid.org/0000-0002-4638-4623)
- L. Nieuwenhuizen
- Paul L. den Exter (ORCID: https://orcid.org/0000-0002-1543-5731)
- Sytze de Bruin (ORCID: https://orcid.org/0000-0002-6884-2832)
- Fleur S. Kleijwegt
- Lisa Hessels (ORCID: https://orcid.org/0000-0002-0564-1064)
- Eline A. Vlot (ORCID: https://orcid.org/0000-0002-3538-8880)
- Rolf T. Urbanus (ORCID: https://orcid.org/0000-0002-1601-9393)
- Behnam Hedayat (ORCID: https://orcid.org/0000-0003-1549-021X)
- Renske H. Olie (ORCID: https://orcid.org/0000-0002-4710-9236)
- P. H. M. Westendorp
- Richard Bruggeman (ORCID: https://orcid.org/0000-0002-3238-8471)
- Tilman M. Hackeng (ORCID: https://orcid.org/0000-0003-0142-0843)
- Massimo Caputo (ORCID: https://orcid.org/0000-0001-7508-0891)
- Coen Maas (ORCID: https://orcid.org/0000-0003-4593-0976)
- Roel Vink
- S.R.S. Ramai
- M. I. A. Ribeiro
- Mettine H.A. Bos (ORCID: https://orcid.org/0000-0002-8164-817X)
- P. M. van der Zee
- Jeroen C.J. Eikenboom (ORCID: https://orcid.org/0000-0002-3268-5759)
- Esther G.M. De Waal
- Firdaouss Boutkourt (ORCID: https://orcid.org/0009-0001-4649-4988)
- Mark T. Kearney (ORCID: https://orcid.org/0000-0002-9376-8814)
- Pim van der Harst (ORCID: https://orcid.org/0000-0002-2713-686X)
- Leon M. van den Toorn
- Barry Rockx (ORCID: https://orcid.org/0000-0003-2463-027X)
- Jan Berg (ORCID: https://orcid.org/0000-0001-6771-4452)
- Daan J.L. van Twist (ORCID: https://orcid.org/0000-0001-8433-8030)
- Marijke Linschoten (ORCID: https://orcid.org/0000-0002-4541-080X)
- H. E. Haerkens-Arends
- P. S. Monraats
- Kirby Tong‐Minh (ORCID: https://orcid.org/0000-0002-8373-0011)
- Mathilde Nijkeuter (ORCID: https://orcid.org/0000-0003-1406-0699)
- Laurence Gabriël (ORCID: https://orcid.org/0000-0002-0816-2317)
- Cees M.P.M. Hertogh (ORCID: https://orcid.org/0000-0003-3081-1245)
- Esther J. Nossent (ORCID: https://orcid.org/0000-0003-3854-4137)
- Matthias Kant (ORCID: https://orcid.org/0000-0001-5090-8234)
- Suzanne C. Cannegieter (ORCID: https://orcid.org/0000-0003-4707-2303)
- Carolina A. M. Schurink (ORCID: https://orcid.org/0000-0002-2766-5147)
- Rosa Macías‐Ruiz (ORCID: https://orcid.org/0000-0003-4686-5678)
- Kristien Winckers (ORCID: https://orcid.org/0000-0003-0478-7157)
- Anton Vonk Noordegraaf (ORCID: https://orcid.org/0000-0002-4057-758X)
- A. M. Alshehri (ORCID: https://orcid.org/0009-0001-0817-6284)
- Chantal Visser (ORCID: https://orcid.org/0000-0002-2025-1734)
- L. S. D. Jewbali
- Iris C.D. Westendorp (ORCID: https://orcid.org/0000-0003-1367-7195)
- Menno V. Huisman (ORCID: https://orcid.org/0000-0003-1423-5348)
- Elias Hellou (ORCID: https://orcid.org/0000-0002-0705-9721)
- Gerry P McCann (ORCID: https://orcid.org/0000-0002-5542-8448)
- H. P. A. A. van Veen
- Emeline M. Van Craenenbroeck (ORCID: https://orcid.org/0000-0001-7686-2668)
- Remy H.H. Bemelmans
- B. Williams (ORCID: https://orcid.org/0009-0008-0245-6470)
- F. J. H. Magdelijns
- Marlies E. Kevenaar
- Jan Westerink (ORCID: https://orcid.org/0000-0001-5021-5227)
- Johan De Sutter (ORCID: https://orcid.org/0000-0003-1433-8152)
- Bas Franken
- Barbara Festen
- Y. A. Almubarak
- Pier Woudstra (ORCID: https://orcid.org/0000-0002-5870-9923)
- Hugo Ten Cate (ORCID: https://orcid.org/0000-0001-7796-4463)
- Derk O. Verschure (ORCID: https://orcid.org/0000-0002-3205-5183)
- Arina J. ten Cate‐Hoek (ORCID: https://orcid.org/0000-0002-9900-6212)
- Eric C. M. Van Gorp (ORCID: https://orcid.org/0000-0001-6415-6678)
- D. J. van de Watering
- Danny Noack (ORCID: https://orcid.org/0000-0003-1845-7511)
- Thijs F. van Haaps (ORCID: https://orcid.org/0000-0002-8358-2426)
- Marcel M.C. Hovens (ORCID: https://orcid.org/0000-0003-4835-5057)
- R. S. Hermanides
- N. Charlotte (ORCID: https://orcid.org/0000-0001-5052-5161)
- Paul M Dark (ORCID: https://orcid.org/0000-0003-3309-0164)
- Dirk J. van der Heijden (ORCID: https://orcid.org/0000-0002-9904-9212)
- Jacqueline G. Hugtenburg (ORCID: https://orcid.org/0000-0001-6098-2438)
- Mohammed Alshahrani (ORCID: https://orcid.org/0000-0001-5946-2128)
- Elena Tessitore (ORCID: https://orcid.org/0000-0003-1680-0152)
- Ruben Bierings (ORCID: https://orcid.org/0000-0002-1205-9689)
- Yvo M. Smulders (ORCID: https://orcid.org/0000-0002-6680-8649)
- Caroline Weytjens
- Henri H. Versteeg (ORCID: https://orcid.org/0000-0003-4294-175X)
- J.J. Miranda Geelhoed (ORCID: https://orcid.org/0000-0002-1296-6668)
- Bart J.M. van Vlijmen (ORCID: https://orcid.org/0000-0003-0208-6453)
- Philippe Timmermans (ORCID: https://orcid.org/0000-0003-4023-615X)
- Brigitte Westerhof
- Evelien Oostdijk
- Corstiaan A. den Uil (ORCID: https://orcid.org/0000-0003-0635-2843)
- J. Burggraaf (ORCID: https://orcid.org/0000-0002-9904-7495)
- Arend Mosterd (ORCID: https://orcid.org/0000-0002-6906-2643)
- Ilse M. Schrover
- Tom W. van de Berg (ORCID: https://orcid.org/0000-0002-7069-7590)
- Astrid Schut (ORCID: https://orcid.org/0000-0001-9397-7109)
- Henrik Endeman (ORCID: https://orcid.org/0000-0002-2011-5169)
- P.R. Nierop
- Eva K Kempers (ORCID: https://orcid.org/0000-0001-9458-8674)
- C. E. Delsing
- Moniek P.M. de Maat (ORCID: https://orcid.org/0000-0001-7749-334X)
- Johanna M. Kwakkel‐van Erp (ORCID: https://orcid.org/0000-0002-7558-1239)
- Rolf E. Brouwer (ORCID: https://orcid.org/0009-0001-5661-3290)
- Leo Heunks (ORCID: https://orcid.org/0000-0003-3196-4665)
- Akbar Shafiee (ORCID: https://orcid.org/0000-0001-6912-7788)
- Todd Kuiken (ORCID: https://orcid.org/0000-0001-7851-6232)
- Bart Spaetgens (ORCID: https://orcid.org/0000-0003-3062-2612)
- Stefanie Koster (ORCID: https://orcid.org/0000-0001-8449-9985)
- Cornelis P. C. de Jager (ORCID: https://orcid.org/0000-0002-2157-4543)
- Coen van Guldener
- Maartje van den Biggelaar (ORCID: https://orcid.org/0000-0001-6970-5496)
- Casper Rokx (ORCID: https://orcid.org/0000-0002-1904-6450)
- Bas C. T. van Bussel (ORCID: https://orcid.org/0000-0003-1621-7848)
- Janise Braga Barros Ferreira (ORCID: https://orcid.org/0000-0001-7480-937X)
- Laura Montagna
- Frederikus Albertus Klok (ORCID: https://orcid.org/0000-0001-9961-0754)
- Pim van der Meer
- G. C. M. Linssen
- Ron Pisters (ORCID: https://orcid.org/0000-0001-8965-0664)
- Kees Kramers
- Janine van Kooten
- F. Nanne Croles (ORCID: https://orcid.org/0000-0001-7722-1862)
- Swati Prasad (ORCID: https://orcid.org/0000-0002-6728-0911)
- Roger E. G. Schutgens (ORCID: https://orcid.org/0000-0002-2762-6033)
- Pieter Roel Tuinman (ORCID: https://orcid.org/0000-0003-4335-5568)
- Robert G Tieleman (ORCID: https://orcid.org/0000-0002-7654-2098)
- Manish Saxena (ORCID: https://orcid.org/0000-0001-9964-2692)
- Y M Pinto
- Nick van Es (ORCID: https://orcid.org/0000-0001-5256-6346)
- Anna H.E. Roukens
- J.F. Hermans-van Ast
- A G Zaman
- Peter Smits
- Clara E E van Ofwegen-Hanekamp (ORCID: https://orcid.org/0009-0007-8844-5862)
- Stéphane Heymans (ORCID: https://orcid.org/0000-0001-9477-7803)
- A. J. M. van Boxem
- Marco Goeijenbier (ORCID: https://orcid.org/0000-0002-3165-8193)
- Daniek A. M. Meijs (ORCID: https://orcid.org/0000-0002-9000-0420)
- Maarten van Smeden (ORCID: https://orcid.org/0000-0002-5529-1541)
- Harald J. Faber
- Annie Cornet (ORCID: https://orcid.org/0000-0002-5015-5532)
- Karina Meijer (ORCID: https://orcid.org/0000-0001-9447-0465)
- Susanne Stads (ORCID: https://orcid.org/0000-0002-9728-4884)
- Anne‐Marije Hulshof (ORCID: https://orcid.org/0000-0001-9688-2324)
- Nicole Hunfeld (ORCID: https://orcid.org/0000-0001-6856-7028)
- Mandy N. Lauw (ORCID: https://orcid.org/0000-0003-0398-3164)
- Leon J. Schurgers (ORCID: https://orcid.org/0000-0001-7867-6957)
- E. Saneei
- Jan Voorberg (ORCID: https://orcid.org/0000-0003-4585-2621)
- Bas de Laat (ORCID: https://orcid.org/0000-0001-9596-1944)
- M. M. J. M. van der Linden
- Lianne R. de Haan
- Angela C. Shore (ORCID: https://orcid.org/0000-0003-3039-308X)
- R. L. Anthonio
- Alexander P. J. Vlaar (ORCID: https://orcid.org/0000-0002-3453-7186)
- Henri M.H. Spronk (ORCID: https://orcid.org/0000-0002-3858-334X)
- Albertus Beishuizen
- Hein Putter (ORCID: https://orcid.org/0000-0001-5395-1422)
- I. van der Lee
- Ton Lisman (ORCID: https://orcid.org/0000-0002-3503-7140)
- Mark J R Smeets (ORCID: https://orcid.org/0000-0001-5296-1151)
- Rehab Salah (ORCID: https://orcid.org/0000-0003-4688-0763)
- Fabrice M A C Martens (ORCID: https://orcid.org/0000-0002-0977-7276)
- Marten R. Nijziel (ORCID: https://orcid.org/0000-0001-9069-4939)
- Jeroen van den Akker (ORCID: https://orcid.org/0000-0002-3071-3410)
- Yvonne Henskens (ORCID: https://orcid.org/0000-0003-0217-6045)
- Brigitte M. Sondermeijer
- Nuray Kuşadasi (ORCID: https://orcid.org/0000-0003-3504-0996)
- Chang-Han Jong
- Saskia le Cessie (ORCID: https://orcid.org/0000-0003-2154-4923)
- Lucia J.M. Kroft (ORCID: https://orcid.org/0000-0002-4734-8616)
- Fahd A Al-Muhanna (ORCID: https://orcid.org/0000-0003-2169-8391)
- Evert‐Jan Wils (ORCID: https://orcid.org/0000-0002-2868-0920)
- Pieter W. Kamphuisen (ORCID: https://orcid.org/0000-0002-6263-0177)
- B. E. Groenemeijer
- Mathijs Raadsen
- A. N. Alnafie
- Araci M. R. Rondon (ORCID: https://orcid.org/0000-0002-2703-8805)
- P. Y. Kopylov
- Avinash Aujayeb (ORCID: https://orcid.org/0000-0002-0859-5550)
- H. A. H. Kaasjager
- Janneke Tijmensen
- Jeroen K. de Vries
- H. A. M. van Kesteren
- M. W. J. van Hessen
- Pim van Montfort (ORCID: https://orcid.org/0000-0001-7292-9810)
- Amein K. Al‐Ali (ORCID: https://orcid.org/0000-0002-0673-3534)
- Milou A.M. Stals (ORCID: https://orcid.org/0000-0003-2328-7705)
- Nicole P. Juffermans (ORCID: https://orcid.org/0000-0002-3039-6574)
- Fleur V.Y. Tjong (ORCID: https://orcid.org/0000-0001-9608-0081)
- Bas Kietselaer (ORCID: https://orcid.org/0000-0002-0096-8594)
- Marije ten Wolde
- Hamidreza Poorhosseini
- Gideon R. Hajer
- Mireille E. Emans
- Olaf L. Cremer (ORCID: https://orcid.org/0000-0003-4264-1108)
- A. C. Reidinga
- Diederik A M P J Gommers (ORCID: https://orcid.org/0000-0001-6808-7702)
- Marcella C.A. Müller (ORCID: https://orcid.org/0000-0002-5309-179X)
- Marieke J.H.A. Kruip
- Diederik van de Beek (ORCID: https://orcid.org/0000-0002-4571-044X)
- Peter Messiaen (ORCID: https://orcid.org/0000-0001-9619-1291)
- J. Leentjes
- A. Stemerdink
- A. Lansbergen
- David P Ripley (ORCID: https://orcid.org/0000-0001-8460-9873)
- Mark M. G. Mulder (ORCID: https://orcid.org/0000-0002-6485-8060)
- Hubert W. Vliegen (ORCID: https://orcid.org/0000-0002-6181-3377)
- I. C. C. van der Horst
- Y.I.G. van Tichelaar
- Renée A. Douma
- Geert-Jan Geersing
- Wim Boersma
- A. Moriarty
- M.K. Ninaber
- Ruben Zaal
- Marco J.J.H. Grootenboers
- J. T. Drost
- Jacobien Ellerbroek
- K. W. Wu
- Folkert W Asselbergs
- Thiemo Veneman
- Jeroen Schaap
- Dirk Schellings
- R. M. A. van de Wal
- M. F. L. Meijs
- N. Y. Y. Al-Windy
- Bram van den Borst
- J. C. M. Meijers
- M. Louisa Antoni (ORCID: https://orcid.org/0000-0003-1831-6698)
- Thirza J. Roest
- Aafke M H Koning
- Joyce Faber
- Frank Stam
- H. G. R. Dorman
- Laura M. Faber
- A. F. M. Kuijper
Institutions
- Leiden University (NL)
- Saint-Gobain (France) (FR)
- University of Leeds (GB)
- University Medical Center Groningen (NL)
- Radboud University Nijmegen (NL)
- University of Antwerp (BE)
- University of Leicester (GB)
- Universitat de València (ES)
- Queen Mary University of London (GB)
- Royal Free London NHS Foundation Trust (GB)
- University of Groningen (NL)
- Sechenov University (RU)
- Utrecht University (NL)
- Benha University (EG)
- University of Exeter (GB)
- Nazareth Hospital EMMS (IL)
- Leiden University Medical Center (NL)
- Maastricht University Medical Centre (NL)
- University Hospitals Bristol NHS Foundation Trust (GB)
- Gelre Hospitals (NL)
- Northumbria Healthcare NHS Foundation Trust (GB)
- Salford Royal NHS Foundation Trust (GB)
- Catharina Ziekenhuis (NL)
- Royal Devon and Exeter Hospital (GB)
- King Fahd Hospital of the University (SA)
- Newcastle upon Tyne Hospitals NHS Foundation Trust (GB)
- Medisch Spectrum Twente (NL)
- Freeman Hospital (GB)
- Erasmus MC (NL)
- Glenfield Hospital (GB)
- Medisch Centrum Leeuwarden (NL)
- Radboud University Medical Center (NL)
- University Medical Center Utrecht (NL)
- Sanquin (NL)
- Ghent University (BE)
- Maastricht University (NL)
- National Institute for Health and Care Research (GB)
- University of Bristol (GB)
- Sint Franciscus Gasthuis (NL)
- Noordwest Ziekenhuisgroep (NL)
- Albert Schweitzer Ziekenhuis (NL)
- VIB-KU Leuven Center for Cancer Biology (BE)
- Slingeland Ziekenhuis (NL)
- Jessa Hospital (BE)
- Rode Kruis Ziekenhuis (NL)
- Royal Brompton Hospital (GB)
- Medisch Centrum Haaglanden (NL)
- Reinier de Graaf Hospital (NL)
- Hospital Prof. Dr. Fernando Fonseca (PT)
- Northwest Hospital (US)
- Antwerp University Hospital (BE)
- Werkgroep Cardiologische centra Nederland (NL)
- St. Antonius Ziekenhuis (NL)
- Ikazia Ziekenhuis (NL)
- Netherlands Heart Institute (NL)
- Amphia Ziekenhuis (NL)
- University Hospital of Geneva (CH)
- Diakonessenhuis hospital (NL)
- Amsterdam Neuroscience (NL)
- Maasstad Ziekenhuis (NL)
- Hospital do Espírito Santo (PT)
- Treant Zorggroep (NL)
- Martini Ziekenhuis (NL)
- Lange Land Ziekenhuis (NL)
- Hospital Universitario Virgen de las Nieves (ES)
- Beatrix Kinderziekenhuis (NL)
- Ziekenhuis Bethesda (NL)
- Ziekenhuis Gelderse Vallei (NL)
- Máxima Medisch Centrum (NL)
- Zaans Medisch Centrum (NL)
- NIHR Exeter Clinical Research Facility (GB)
- Synapse (Netherlands) (NL)
- Zuyderland Medisch Centrum (NL)
- Groene Hart Ziekenhuis (NL)
- AZ Maria Middelares (BE)
- Ziekenhuis Amstelland (NL)
- Isala (NL)
- Tergooi (NL)
- Federatie Medisch Specialisten (NL)
- Elisabeth-TweeSteden Ziekenhuis (NL)
- Ziekenhuis Groep Twente (NL)
- Erasmus MC Cancer Institute (NL)
- William Harvey Research Institute (GB)
- Franciscus Vlietland (NL)
- Admiraal De Ruyter Ziekenhuis (NL)
- Amsterdam University Medical Centers (NL)
- Rijnstate Hospital (NL)
- Ospedale San Luigi Gonzaga (IT)
- Deventer Ziekenhuis (NL)
- Ziekenhuis Bernhoven (NL)
- Medisch Centrum Alkmaar (NL)
- INCLIVA Health Research Institute (ES)
- Meander Medisch Centrum (NL)
- Jeroen Bosch Ziekenhuis (NL)
- Bravis Ziekenhuis (NL)
- Spaarne Gasthuis (NL)
- University Hospitals Bristol and Weston NHS Foundation Trust (GB)
- University College London (GB)
- Imperial College London (GB)
- Tehran University of Medical Sciences (IR)
- Imam Abdulrahman Bin Faisal University (SA)
- Newcastle University (GB)
- Vrije Universiteit Amsterdam (NL)
- Hasselt University (BE)
- University of Amsterdam (NL)
- Erasmus University Rotterdam (NL)
- UCLouvain (BE)
Publication Details
- Journal
- Scientific Reports
- Published
- 2025-03-25
- DOI
- https://doi.org/10.1038/s41598-024-77858-w
- Citations
- 1
- Primary Topic
- COVID-19 Clinical Research Studies
- Type
- article
- Field-Weighted Citation Impact
- 1.40
Funders
- Sanofi
- Alexion Pharmaceuticals
- CSL Behring
- Society for Cardiovascular Magnetic Resonance
- Dutch Cardiovascular Alliance
- National Institute for Health and Care Research
- British Heart Foundation
- University College London
- European Society of Cardiology
- ZonMw
- Novo Nordisk
- EuroQol Research Foundation
- Servier
- Trombosestichting Nederland
- Swedish Orphan Biovitrum
- InflaRx
- Sanofi Genzyme
- Daiichi Sankyo Europe