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Research paper
Heparin for prophylaxis of venous thromboembolism in intracerebral haemorrhage
  1. Maximilian I Sprügel1,
  2. Jochen A Sembill1,
  3. Joji B Kuramatsu1,
  4. Stefan T Gerner1,
  5. Manuel Hagen1,
  6. Sebastian S Roeder1,
  7. Matthias Endres2,
  8. Karl Georg Haeusler2,
  9. Jan Sobesky2,
  10. Johannes Schurig2,
  11. Sarah Zweynert2,
  12. Miriam Bauer2,
  13. Peter Vajkoczy3,
  14. Peter Arthur Ringleb4,
  15. Jan Christoph Purrucker4,
  16. Timolaos Rizos4,
  17. Jens Volkmann5,
  18. Wolfgang Muellges5,
  19. Peter Kraft5,
  20. Anna-Lena Schubert5,
  21. Frank Erbguth6,
  22. Martin Nueckel6,
  23. Peter D Schellinger7,
  24. Jörg Glahn7,
  25. Ulrich J Knappe8,
  26. Gereon Rudolf Fink9,
  27. Christian Dohmen9,
  28. Henning Stetefeld9,
  29. Anna Lena Fisse10,
  30. Jens Minnerup10,
  31. Georg Hagemann11,
  32. Florian Rakers11,
  33. Heinz Reichmann12,
  34. Hauke Schneider12,
  35. Sigrid Wöpking12,
  36. Albert C Ludolph13,
  37. Sebastian Stösser13,
  38. Hermann Neugebauer13,
  39. Joachim Röther14,
  40. Peter Michels14,
  41. Michael Schwarz15,
  42. Gernot Reimann15,
  43. Hansjörg Bäzner16,
  44. Henning Schwert16,
  45. Joseph Classen17,
  46. Dominik Michalski17,
  47. Armin Grau18,
  48. Frederick Palm18,
  49. Christian Urbanek18,
  50. Johannes C Wöhrle19,
  51. Fahid Alshammari19,
  52. Markus Horn20,
  53. Dirk Bahner20,
  54. Otto W Witte21,
  55. Albrecht Guenther21,
  56. Gerhard F Hamann22,
  57. Hannes Lücking23,
  58. Arnd Dörfler23,
  59. Stefan Schwab1,
  60. Hagen B Huttner1
  1. 1 Neurology, University of Erlangen-Nürnberg, Erlangen, Germany
  2. 2 Neurology, Charité-Universitätsmedizin Berlin, Berlin, Germany
  3. 3 Neurosurgery, Charité-Universitäts medizin Berlin, Berlin, Germany
  4. 4 Neurology, University of Heidelberg, Heidelberg, Germany
  5. 5 Neurology, University of Würzburg, Würzburg, Germany
  6. 6 Neurology, Paracelsus Medical University, Nürnberg, Germany
  7. 7 Neurology, Johannes Wesling Medical Center, Ruhr University Bochum, Minden, Germany
  8. 8 Neurosurgery, Johannes Wesling Medical Center, Ruhr University Bochum, Minden, Germany
  9. 9 Neurology, University of Cologne, Köln, Germany
  10. 10 Neurology, University of Münster, Münster, Germany
  11. 11 Neurology, Community Hospital Berlin-Buch, Berlin, Germany
  12. 12 Neurology, University of Dresden, Dresden, Germany
  13. 13 Neurology, University of Ulm, Ulm, Germany
  14. 14 Neurology, Community Hospital Hamburg Altona, Hamburg, Germany
  15. 15 Neurology, Community Hospital Dortmund, Dortmund, Germany
  16. 16 Neurology, Community Hospital Stuttgart, Stuttgart, Germany
  17. 17 Neurology, University of Leipzig, Leipzig, Germany
  18. 18 Neurology, Community Hospital Ludwigshafen, Ludwigshafen, Germany
  19. 19 Neurology, Community Hospital Koblenz, Koblenz, Germany
  20. 20 Neurology, Community Hospital Bad Hersfeld, Bad Hersfeld, Germany
  21. 21 Neurology, University of Jena, Jena, Germany
  22. 22 Neurology, Community Hospital Günzburg, Günzburg, Germany
  23. 23 Neuroradiology, University of Erlangen-Nürnberg, Erlangen, Germany
  1. Correspondence to Dr Hagen B Huttner, Neurology, University of Erlangen-Nürnberg, Erlangen 91052, Germany; hagen.huttner{at}


Objective To determine the occurrence of intracranial haemorrhagic complications (IHC) on heparin prophylaxis (low-dose subcutaneous heparin, LDSH) in primary spontaneous intracerebral haemorrhage (ICH) (not oral anticoagulation-associated ICH, non-OAC-ICH), vitamin K antagonist (VKA)-associated ICH and non-vitamin K antagonist oral anticoagulant (NOAC)-associated ICH.

Methods Retrospective cohort study (RETRACE) of 22 participating centres and prospective single-centre study with 1702 patients with VKA-associated or NOAC-associated ICH and 1022 patients with non-OAC-ICH with heparin prophylaxis between 2006 and 2015. Outcomes were defined as rates of IHC during hospital stay among patients with non-OAC-ICH, VKA-ICH and NOAC-ICH, mortality and functional outcome at 3 months between patients with ICH with and without IHC.

Results IHC occurred in 1.7% (42/2416) of patients with ICH. There were no differences in crude incidence rates among patients with VKA-ICH, NOAC-ICH and non-OAC-ICH (log-rank p=0.645; VKA-ICH: 27/1406 (1.9%), NOAC-ICH 1/130 (0.8%), non-OAC-ICH 14/880 (1.6%); p=0.577). Detailed analysis according to treatment exposure (days with and without LDSH) revealed no differences in incidence rates of IHC per 1000 patient-days (LDSH: 1.43 (1.04–1.93) vs non-LDSH: 1.32 (0.33–3.58), conditional maximum likelihood incidence rate ratio: 1.09 (0.38–4.43); p=0.953). Secondary outcomes showed differences in functional outcome (modified Rankin Scale=4–6: IHC: 29/37 (78.4%) vs non-IHC: 1213/2048 (59.2%); p=0.019) and mortality (IHC: 14/37 (37.8%) vs non-IHC: 485/2048 (23.7%); p=0.045) in disfavour of patients with IHC. Small ICH volume (OR: volume <4.4 mL: 0.18 (0.04–0.78); p=0.022) and low National Institutes of Health Stroke Scale (NIHSS) score on admission (OR: NIHSS <4: 0.29 (0.11–0.78); p=0.014) were significantly associated with fewer IHC.

Conclusions Heparin administration for venous thromboembolism (VTE) prophylaxis in patients with ICH appears to be safe regarding IHC among non-OAC-ICH, VKA-ICH and NOAC-ICH in this observational cohort analysis. Randomised controlled trials are needed to verify the safety and efficacy of heparin compared with other methods for VTE prevention.

  • intracerebral heamorrhage
  • cerebrovascular disease
  • stroke
  • critical care

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  • MIS, JAS and JBK contributed equally.

  • Correction notice This article has been corrected since it was published. Minor changes have been made to correct the affiliations.

  • Contributors Study concept and design: MIS, JAS, JBK, HBH. Acquisition, analysis or interpretation of data: All authors. Drafting of the manuscript: MIS, JAS, JBK, SS, HBH. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: MIS, JAS, JBK, HBH (University of Erlangen-Nuremberg).

  • Funding The study was partly funded by Covidien/Medtronic/Cardinal Health as successive owners of the Kendall SCDTM Compression product line.

  • Competing interests JBK reports grants from Covidien (Medtronic), personal fees from Bayer, Pfizer and Sanofi. ME reports grants and other from Bayer, other from Boehringer Ingelheim, BMS/Pfizer and Daiichi Sankyo during the conduct of the study; grants from DFG, BMBF, EU, Corona Foundation and Fondation Leducq, other from Amgen, GSK, Novartis, Sanofi and Covidien. KGH reports grants and personal fees from Bayer, personal fees from Daiichi Sankyo, BMS, Pfizer, Boehringer Ingelheim, Sanofi-Aventis and Edwards Lifesciences, non-financial support from Getemed, personal fees from EIP Pharma and Medtronic. JS reports personal fees from Bayer, Pfizer/BMS, Daiichi and Boehringer Ingelheim. PAR reports personal fees from Boehringer Ingelheim, Bayer, Daiichi Sankyo and Pfizer. JCP reports personal fees from Boehringer Ingelheim and Pfizer. TR reports personal fees from BMS Pfizer, Bayer Healthcare, Daiichi Sankyo and Boehringer Ingelheim. JV reports grants from Medtronic and Boston Scientific and fees from Medtronic, St Jude, Boston Scientific, UCB, Merz, Allergan, Teva, Novartis and AbbVie. WM reports personal fees from Boehringer Ingelheim and Bayer Pharma. PK reports personal fees from Bayer, Boehringer Ingelheim, Daiichi Sankyo and Pfizer/Bristol-Myers Squibb. FE reports grants and personal fees from Boehringer Ingelheim, personal fees from Bayer Pharma, Pfizer Pharma, Bristol-Myers Squibb and Daiichi Sankyo. MN reports personal fees from Speaker’s fee Pfizer/BMS and Boehringer Ingelheim. PDS reports personal fees from Boehringer Ingelheim, Bayer, BMS/Pfizer, Daiichi and Medtronic. JG reports personal fees from Pfizer. UJK reports other from Daiichi Sankyo and Bayer. GRF reports personal fees from Bayer and Boehringer. CD reports speaking fees from Bayer, UCB, Daiichi Sankyo and Pfizer. JM reports personal fees from Boehringer Ingelheim and Bayer Healthcare. HN reports personal fees from Boehringer Ingelheim and Daiichi. JR reports personal fees from Bayer, Boehringer, Pfizer and Bristol Myers Squibb. MS reports grants from Deutsche Forschungsgemeinschaft (DFG), Bundesministerium für Bildung und Forschung (BMBF), and the European Union (EU) and fees from Bristol-Myers Squibb, GlaxoSmithKline, Merz Pharmaceuticals, Novartis Pharma, Orion Pharma, Pharmacia, Roche, Sanofi, Teva Pharma and UCB Pharma. GR reports personal fees from Boehringer Ingelheim, Pfizer and Bayer, grants from Daiichi. HB reports personal fees from Honoraria for lectures from Bayer Vital, Boehringer Ingelheim, Bristol-Myers Squibb and Daiichi Sankyo. HS reports grants from Bayer Healthcare. FP reports personal fees from Pfizer/BMS, Bayer, Boehringer Ingelheim and Daiichi Sankyo. JCW reports personal fees from Boehringer Ingelheim Pharma GmbH & Co. KGH reports personal fees from Daiichi Sankyo Pharma. AG reports personal fees from Daiichi Sankyo, Bayer, Boehringer Ingelheim and Bristol-Myers Squibb/Pfizer. GFH reports participation in the Respect-ESUS trial. SS reports personal fees from Boehringer Ingelheim and grants from Daiichi. HBH reports personal fees from Boehringer Ingelheim, Daiichi Sankyo and Novartis, grants from Medtronic.

  • Patient consent for publication Obtained.

  • Ethics approval The study was approved by the local ethics committees and institutional review boards based on the central vote from Friedrich-Alexander-University Erlangen-Nuremberg, Germany (Registration No 4409 and 30_16B, 115_17B).

  • Provenance and peer review Not commissioned; externally peer reviewed.