Improving Outcome in Subarachnoid Hemorrhage wIth Nadroparine

NCT04507178 | Recruiting Phase 2 DMC

• 1 other identifier: NL65235.018.18
• Study Type: interventional
• Target: 100
• Locations: 1 country
• Sites: 1

Brief Summary

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) was long thought to be caused by subarachnoid blood-induced vasospasm. Experimental and clinical evidence suggest activation of several pathophysiological pathways, affecting the cerebral microcirculation. Recently, lower in-hospital mortality and less non-home discharge was reported in patients treated with therapeutic low-molecular weight heparin (LMWH), compared to patients with standard, prophylactic LMWH, pointing towards a potential benefit of higher doses of LMWH in the acute course after aSAH. Treatment with therapeutic LMWH might improve clinical outcome in endovascularly treated aSAH patients. The primary objective is to evaluate whether aSAH patients treated with therapeutic LMWH have a lower 30-day mortality rate compared to patients treated with prophylactic LMWH. Secondary objectives are to evaluate whether there are significant differences between patients treated with therapeutic and prophylactic LMWH in development of DCI, (hemorrhagic) complications during admission, hydrocephalus, non-home discharge location, quality of life, clinical outcome and cognitive functioning at three and six months, total health care costs. A single center, prospective, phase II randomized clinical trial in aneurysmal SAH patients ≥18 years old, in whom the causative aneurysm is treated with endovascular coiling less than 72 hours after initial SAH. Patients are randomized into 2 groups: (1) Therapeutic dose LMWH group: the standard prophylactic dose, administered upon hospital admission, will be replaced by nadroparin s.c. twice daily 5700 IE anti-Xa, starting within 24 hours after coiling and continued until 21 days after ictus of initial SAH. After 21 days, patients will continue with standard care prophylactic dose until discharge or when mobilized for more than 6 hours per day; (2) Control group: standard of care treatment with prophylactic dose of LMWH; nadroparin, s.c. once daily 2850 AxaIU until discharge or when mobilized for at least 6 hours a day. Primary outcome: 30-days' mortality. Secondary outcome: DCI, venous thrombo-embolic complications, occurrence of major and non-major bleeding, hemorrhagic complications after external ventricular/lumbar drain (EVD/ELD) placement and lumbar puncture (LP), other SAH-related complications, shunt-dependent hydrocephalus, discharge location, quality of life, total health care costs, cognitive functioning, clinical outcome.

Conditions

Aneurysmal Subarachnoid Hemorrhage; Delayed Cerebral Ischemia

Keywords

nadroparin; subarachnoid hemorrhage; brain ischemia; delayed cerebral ischemia

Outcome Measures

Primary Outcomes (1)

• mortality rate

  number of patients who have died within 30 days after initial bleeding

  30 days

Secondary Outcomes (9)

• Delayed Cerebral Ischemia

  21 days

• bleedings

  21 days

• hemorrhagic complications

  21 days

• SAH-related complications

  21 days

• hydrocephalus

  6 months

Study Arms (2)

prophylactic dose LMWH

NO INTERVENTION

Patients assigned to the control group will receive standard care according to current protocol with a prophylactic dose of LMWH (nadroparin once daily 2850 AxaIE subcutaneously) starting within 24 hours after coiling, continued until discharge or when mobilized for at least six hours a day.

therapeutic dose LMWH

ACTIVE COMPARATOR

In the intervention group, the standard prophylactic dose will be replaced by a higher dose of LMWH (nadroparin; twice daily 5700 IE) starting within 24 hours after coiling and continued for 21 days after initial SAH. After this, patients will continue with standard care (prophylactic dose until discharge or when mobilized for more than six hours per day).

Drug: Nadroparin Injectable Product

Interventions

Nadroparin Injectable Product DRUG

high dose LMWH compared to prophylactic dose LMWH

Also known as: fraxiparin

therapeutic dose LMWH

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• SAH confirmed by CT or lumbar puncture with the causative aneurysm confirmed by CT-A and/or digital subtraction angiography
• Coiling of the causative aneurysm within 72 hours of initial SAH
• Informed consent within 24 hours after coiling

You may not qualify if:

• Stent-assisted coiling
• Use of anticoagulant medication post-coiling for other reasons
• Contra-indications for LMWH:
• Previous history of history of heparin-induced thrombocytopenia
• (Suspicion of) active arterial or venous bleeding
• Previous history of hemorrhagic diathesis due to coagulation disorders (with the ex-ception of disseminated intravascular coagulation)
• Severe hypertension: uncontrolled hypertension with a mean arterial pressure \>135mmHg
• Previous history of hypertensive or diabetic retinopathy
• Previous history of active infectious endocarditis
• Severe renal impairment (creatinine clearance \<30 mL / min)
• No proficiency of Dutch or English language

Sponsors & Collaborators

• Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA): lead

Study Sites (1)

Amsterdam University Medical Centers

Amsterdam, 1087HV, Netherlands

RECRUITING

Related Publications (32)

• D'Souza S. Aneurysmal Subarachnoid Hemorrhage. J Neurosurg Anesthesiol. 2015 Jul;27(3):222-40. doi: 10.1097/ANA.0000000000000130.

  PMID: 25272066 BACKGROUND

• Johnston SC, Selvin S, Gress DR. The burden, trends, and demographics of mortality from subarachnoid hemorrhage. Neurology. 1998 May;50(5):1413-8. doi: 10.1212/wnl.50.5.1413.

  PMID: 9595997 BACKGROUND

• Molyneux AJ, Birks J, Clarke A, Sneade M, Kerr RS. The durability of endovascular coiling versus neurosurgical clipping of ruptured cerebral aneurysms: 18 year follow-up of the UK cohort of the International Subarachnoid Aneurysm Trial (ISAT). Lancet. 2015 Feb 21;385(9969):691-7. doi: 10.1016/S0140-6736(14)60975-2. Epub 2014 Oct 28.

  PMID: 25465111 BACKGROUND

• Budohoski KP, Guilfoyle M, Helmy A, Huuskonen T, Czosnyka M, Kirollos R, Menon DK, Pickard JD, Kirkpatrick PJ. The pathophysiology and treatment of delayed cerebral ischaemia following subarachnoid haemorrhage. J Neurol Neurosurg Psychiatry. 2014 Dec;85(12):1343-53. doi: 10.1136/jnnp-2014-307711. Epub 2014 May 20.

  PMID: 24847164 BACKGROUND

• Vergouwen MD, Vermeulen M, Coert BA, Stroes ES, Roos YB. Microthrombosis after aneurysmal subarachnoid hemorrhage: an additional explanation for delayed cerebral ischemia. J Cereb Blood Flow Metab. 2008 Nov;28(11):1761-70. doi: 10.1038/jcbfm.2008.74. Epub 2008 Jul 16.

  PMID: 18628782 BACKGROUND

• Hayman EG, Patel AP, James RF, Simard JM. Heparin and Heparin-Derivatives in Post-Subarachnoid Hemorrhage Brain Injury: A Multimodal Therapy for a Multimodal Disease. Molecules. 2017 May 2;22(5):724. doi: 10.3390/molecules22050724.

  PMID: 28468328 BACKGROUND

• Rowland MJ, Hadjipavlou G, Kelly M, Westbrook J, Pattinson KT. Delayed cerebral ischaemia after subarachnoid haemorrhage: looking beyond vasospasm. Br J Anaesth. 2012 Sep;109(3):315-29. doi: 10.1093/bja/aes264.

  PMID: 22879655 BACKGROUND

• Young E. The anti-inflammatory effects of heparin and related compounds. Thromb Res. 2008;122(6):743-52. doi: 10.1016/j.thromres.2006.10.026. Epub 2007 Aug 28.

  PMID: 17727922 BACKGROUND

• Blasberg R, Johnson D, Fenstermacher J. Absorption resistance of cerebrospinal fluid after subarachnoid hemorrhage in the monkey; effects of heparin. Neurosurgery. 1981 Dec;9(6):686-91. doi: 10.1227/00006123-198112000-00012.

  PMID: 7322334 BACKGROUND

• Kapp JP, Neill WR, Neill CL, Hodges LR, Smith RR. The three phases of vasospasm. Surg Neurol. 1982 Jul;18(1):40-5. doi: 10.1016/0090-3019(82)90011-8.

  PMID: 7112386 BACKGROUND

• Chimowitz MI, Pessin MS. Is there a role for heparin in the management of complications of subarachnoid hemorrhage? Stroke. 1987 Nov-Dec;18(6):1169-72. doi: 10.1161/01.str.18.6.1169.

  PMID: 3318003 BACKGROUND

• Yamamoto Y, Smith RR, Bernanke DH. Accelerated nonmuscle contraction after subarachnoid hemorrhage: culture and characterization of myofibroblasts from human cerebral arteries in vasospasm. Neurosurgery. 1992 Mar;30(3):337-45. doi: 10.1227/00006123-199203000-00005.

  PMID: 1620295 BACKGROUND

• Tekkok IH, Tekkok S, Ozcan OE, Erbengi T, Erbengi A. Preventive effect of intracisternal heparin for proliferative angiopathy after experimental subarachnoid haemorrhage in rats. Acta Neurochir (Wien). 1994;127(1-2):112-7. doi: 10.1007/BF01808557.

  PMID: 7524276 BACKGROUND

• Mary V, Wahl F, Uzan A, Stutzmann JM. Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity. Stroke. 2001 Apr;32(4):993-9. doi: 10.1161/01.str.32.4.993.

  PMID: 11283402 BACKGROUND

• Stutzmann JM, Mary V, Wahl F, Grosjean-Piot O, Uzan A, Pratt J. Neuroprotective profile of enoxaparin, a low molecular weight heparin, in in vivo models of cerebral ischemia or traumatic brain injury in rats: a review. CNS Drug Rev. 2002 Spring;8(1):1-30. doi: 10.1111/j.1527-3458.2002.tb00213.x.

  PMID: 12070524 BACKGROUND

• Zhang ZG, Lu TS, Yuan HY. Neuroprotective effects of ultra-low-molecular-weight heparin in vitro and vivo models of ischemic injury. Fundam Clin Pharmacol. 2011 Jun;25(3):300-3. doi: 10.1111/j.1472-8206.2010.00845.x.

  PMID: 20608997 BACKGROUND

• Simard JM, Tosun C, Ivanova S, Kurland DB, Hong C, Radecki L, Gisriel C, Mehta R, Schreibman D, Gerzanich V. Heparin reduces neuroinflammation and transsynaptic neuronal apoptosis in a model of subarachnoid hemorrhage. Transl Stroke Res. 2012 Jul;3(Suppl 1):155-65. doi: 10.1007/s12975-012-0166-9. Epub 2012 Apr 14.

  PMID: 22707992 BACKGROUND

• Simard JM, Schreibman D, Aldrich EF, Stallmeyer B, Le B, James RF, Beaty N. Unfractionated heparin: multitargeted therapy for delayed neurological deficits induced by subarachnoid hemorrhage. Neurocrit Care. 2010 Dec;13(3):439-49. doi: 10.1007/s12028-010-9435-1.

  PMID: 20809188 BACKGROUND

• Yan Y, Ji Y, Su N, Mei X, Wang Y, Du S, Zhu W, Zhang C, Lu Y, Xing XH. Non-anticoagulant effects of low molecular weight heparins in inflammatory disorders: A review. Carbohydr Polym. 2017 Mar 15;160:71-81. doi: 10.1016/j.carbpol.2016.12.037. Epub 2016 Dec 21.

  PMID: 28115102 BACKGROUND

• Hochart H, Jenkins PV, Smith OP, White B. Low-molecular weight and unfractionated heparins induce a downregulation of inflammation: decreased levels of proinflammatory cytokines and nuclear factor-kappaB in LPS-stimulated human monocytes. Br J Haematol. 2006 Apr;133(1):62-7. doi: 10.1111/j.1365-2141.2006.05959.x.

  PMID: 16512830 BACKGROUND

• Siironen J, Juvela S, Varis J, Porras M, Poussa K, Ilveskero S, Hernesniemi J, Lassila R. No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial. J Neurosurg. 2003 Dec;99(6):953-9. doi: 10.3171/jns.2003.99.6.0953.

  PMID: 14705720 BACKGROUND

• Wurm G, Tomancok B, Nussbaumer K, Adelwohrer C, Holl K. Reduction of ischemic sequelae following spontaneous subarachnoid hemorrhage: a double-blind, randomized comparison of enoxaparin versus placebo. Clin Neurol Neurosurg. 2004 Mar;106(2):97-103. doi: 10.1016/j.clineuro.2004.01.006.

  PMID: 15003298 BACKGROUND

• Simard JM, Aldrich EF, Schreibman D, James RF, Polifka A, Beaty N. Low-dose intravenous heparin infusion in patients with aneurysmal subarachnoid hemorrhage: a preliminary assessment. J Neurosurg. 2013 Dec;119(6):1611-9. doi: 10.3171/2013.8.JNS1337. Epub 2013 Sep 13.

  PMID: 24032706 BACKGROUND

• Bruder M, Won SY, Kashefiolasl S, Wagner M, Brawanski N, Dinc N, Seifert V, Konczalla J. Effect of heparin on secondary brain injury in patients with subarachnoid hemorrhage: an additional 'H' therapy in vasospasm treatment. J Neurointerv Surg. 2017 Jul;9(7):659-663. doi: 10.1136/neurintsurg-2016-012925. Epub 2017 Feb 2.

  PMID: 28153852 BACKGROUND

• van Roessel S, Middeldorp S, Cheung YW, Zwinderman AH, de Pont AC. Accuracy of aPTT monitoring in critically ill patients treated with unfractionated heparin. Neth J Med. 2014 Jul;72(6):305-10.

  PMID: 25319855 BACKGROUND

• Post R, Zijlstra IAJ, Berg RVD, Coert BA, Verbaan D, Vandertop WP. High-Dose Nadroparin Following Endovascular Aneurysm Treatment Benefits Outcome After Aneurysmal Subarachnoid Hemorrhage. Neurosurgery. 2018 Aug 1;83(2):281-287. doi: 10.1093/neuros/nyx381.

  PMID: 28945859 BACKGROUND

• Bruder M, Schuss P, Konczalla J, El-Fiki A, Lescher S, Vatter H, Seifert V, Guresir E. Ventriculostomy-Related Hemorrhage After Treatment of Acutely Ruptured Aneurysms: The Influence of Anticoagulation and Antiplatelet Treatment. World Neurosurg. 2015 Dec;84(6):1653-9. doi: 10.1016/j.wneu.2015.07.003. Epub 2015 Jul 13.

  PMID: 26183133 BACKGROUND

• Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, Mendelow AD, Juvela S, Yonas H, Terbrugge KG, Macdonald RL, Diringer MN, Broderick JP, Dreier JP, Roos YB. Definition of delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage as an outcome event in clinical trials and observational studies: proposal of a multidisciplinary research group. Stroke. 2010 Oct;41(10):2391-5. doi: 10.1161/STROKEAHA.110.589275. Epub 2010 Aug 26.

  PMID: 20798370 BACKGROUND

• Nasreddine ZS, Phillips NA, Bedirian V, Charbonneau S, Whitehead V, Collin I, Cummings JL, Chertkow H. The Montreal Cognitive Assessment, MoCA: a brief screening tool for mild cognitive impairment. J Am Geriatr Soc. 2005 Apr;53(4):695-9. doi: 10.1111/j.1532-5415.2005.53221.x.

  PMID: 15817019 BACKGROUND

• RANKIN J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957 May;2(5):200-15. doi: 10.1177/003693305700200504. No abstract available.

  PMID: 13432835 BACKGROUND

• Schweizer TA, Al-Khindi T, Macdonald RL. Mini-Mental State Examination versus Montreal Cognitive Assessment: rapid assessment tools for cognitive and functional outcome after aneurysmal subarachnoid hemorrhage. J Neurol Sci. 2012 May 15;316(1-2):137-40. doi: 10.1016/j.jns.2012.01.003. Epub 2012 Jan 26.

  PMID: 22280947 BACKGROUND

• Denneman N, Doorschodt TC, Coert BA, van den Berg R, Majoie CBLM, Muller MCA, Middeldorp S, Coppens M, Kempeneers MA, Tjerkstra MA, Labib H, Bandral HV, Baarse M, Platek EE, Vandertop WP, Verbaan D, Post R. Improving outcome in SubaraChnoid HEMorrhage wIth nAdroparin (ISCHEMIA): a prospective randomised controlled trial protocol. BMJ Open. 2025 Aug 28;15(8):e096555. doi: 10.1136/bmjopen-2024-096555.

  PMID: 40876884 DERIVED

MeSH Terms

Conditions

Subarachnoid Hemorrhage; Brain Ischemia

Interventions

Nadroparin

Condition Hierarchy (Ancestors)

Intracranial Hemorrhages; Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Hemorrhage; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Heparin, Low-Molecular-Weight; Heparin; Glycosaminoglycans; Polysaccharides; Carbohydrates

Study Officials

• William P Vandertop, MD PhD

  Amsterdam UMC

  STUDY CHAIR

Central Study Contacts

Dagmar Verbaan, PhD

CONTACT

+31205663316; d.verbaan@amsterdamumc.nl

William P Vandertop, MD PhD

CONTACT

+31205669111; wp.vandertop@amsterdamumc.nl

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: single blind
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: chair neurosurgery

Model Details: A single center, single blind, prospective, phase II randomized clinical trial.

Study Record Dates

• First Submitted: August 7, 2020
• First Posted: August 11, 2020
• Study Start: February 2, 2022
• Primary Completion (Estimated): August 1, 2026
• Study Completion (Estimated): April 1, 2027
• Last Updated: January 29, 2025

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

NL (1)