No effect of enoxaparin on outcome of aneurysmal subarachnoid hemorrhage: a randomized, double-blind, placebo-controlled clinical trial

Restricted access

Object. From the moment an intracranial aneurysm ruptures, cerebral blood flow is impaired, and this impairment mainly determines the outcome in patients who survive after the initial bleeding. The exact mechanism of impairment is unknown, but activation of coagulation and fibrinolysis correlate with clinical condition and outcome after aneurysmal subarachnoid hemorrhage (SAH). The purpose of this study was to determine whether enoxaparin, a low-molecular-weight heparin, which is a well-known anticoagulating agent, has any effect on the outcome of aneurysmal SAH postoperatively.

Methods. In this randomized, double-blind, single-center clinical trial, 170 patients (85 per group) with aneurysmal SAH were randomly assigned to receive either enoxaparin (40 mg subcutaneously once daily) or a placebo, starting within 24 hours after occlusion of the aneurysm and continuing for 10 days. Analysis was done on an intention-to-treat basis. Outcome was assessed at 3 months on both the Glasgow Outcome and modified Rankin Scales. Patients were eligible for the study if surgery was performed within 48 hours post-SAH, and no intracerebral hemorrhage was larger than 20 mm in diameter on the first postoperative computerized tomography scan.

At 3 months, there were no significant differences in outcome by treatment group. Of the 170 patients, 11 (6%) died, and only 95 (56%) had a good outcome. Principal causes of unfavorable outcome were poor initial condition, delayed cerebral ischemia, and surgical complications. There were four patients with additional intracranial bleeding in the group receiving enoxaparin. The bleeding was not necessarily associated with the treatment itself, nor did it require treatment, and there were no such patients in the placebo group.

Conclusions. Enoxaparin seemed to have no effect on the outcome of aneurysmal SAH in patients who had already received routine nimodipine and who had received triple-H therapy when needed. Routine use of low-molecular-weight heparin should be avoided during the early postoperative period in patients with SAH, because this agent seems to increase intracranial bleeding complications slightly, with no beneficial effect on neurological outcome.

Article Information

Address reprint requests to: Jari Siironen, M.D., Ph.D., Department of Neurosurgery, Helsinki University Central Hospital, Topeliuksenkatu 5, FIN-00260 Helsinki 26, Finland. email: jari.siironen@hus.fi.

© AANS, except where prohibited by US copyright law.

Headings

References

  • 1.

    Agnelli GPiovella FBuoncristiani Pet al: Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 339:80851998Agnelli G Piovella F Buoncristiani P et al: Enoxaparin plus compression stockings compared with compression stockings alone in the prevention of venous thromboembolism after elective neurosurgery. N Engl J Med 339:80–85 1998

  • 2.

    Anonymous: United Kingdom transient ischaemic attack (UKTIA) aspirin trial: interim results. Br Med J 296:3163201988Anonymous: United Kingdom transient ischaemic attack (UKTIA) aspirin trial: interim results. Br Med J 296:316–320 1988

  • 3.

    Bergqvist DAgnelli GCohen ATet al: Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 346:9759802002Bergqvist D Agnelli G Cohen AT et al: Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 346:975–980 2002

  • 4.

    Bergqvist DBenoni GBjorgell Oet al: Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 335:6967001996Bergqvist D Benoni G Bjorgell O et al: Low-molecular-weight heparin (enoxaparin) as prophylaxis against venous thromboembolism after total hip replacement. N Engl J Med 335:696–700 1996

  • 5.

    Brott TBogousslavsky J: Treatment of acute ischemic stroke. N Engl J Med 343:7107222000Brott T Bogousslavsky J: Treatment of acute ischemic stroke. N Engl J Med 343:710–722 2000

  • 6.

    Dale JLandmark KHMyhre E: The effects of nifedipine, a calcium antagonist, on platelet function. Am Heart J 105:1031051983Dale J Landmark KH Myhre E: The effects of nifedipine a calcium antagonist on platelet function. Am Heart J 105:103–105 1983

  • 7.

    Dickinson LDMiller LDPatel CPet al: Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery 43:107410811998Dickinson LD Miller LD Patel CP et al: Enoxaparin increases the incidence of postoperative intracranial hemorrhage when initiated preoperatively for deep venous thrombosis prophylaxis in patients with brain tumors. Neurosurgery 43:1074–1081 1998

  • 8.

    Fisher CMKistler JPDavis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:191980Fisher CM Kistler JP Davis JM: Relation of cerebral vasospasm to subarachnoid hemorrhage visualized by computerized tomographic scanning. Neurosurgery 6:1–9 1980

  • 9.

    Fridriksson SSaveland HJakobsson KEet al: Intraoperative complications in aneurysm surgery: a prospective national study. J Neurosurg 96:5155222002Fridriksson S Saveland H Jakobsson KE et al: Intraoperative complications in aneurysm surgery: a prospective national study. J Neurosurg 96:515–522 2002

  • 10.

    Fujii YTakeuchi SSasaki Oet al: Serial changes of hemostasis in aneurysmal subarachnoid hemorrhage with special reference to delayed ischemic neurological deficits. J Neurosurg 86:5946021997Fujii Y Takeuchi S Sasaki O et al: Serial changes of hemostasis in aneurysmal subarachnoid hemorrhage with special reference to delayed ischemic neurological deficits. J Neurosurg 86:594–602 1997

  • 11.

    Hamilton MGHull RDPineo GF: Venous thromboembolism in neurosurgery and neurology patients: a review. Neurosurgery 34:2802961994Hamilton MG Hull RD Pineo GF: Venous thromboembolism in neurosurgery and neurology patients: a review. Neurosurgery 34:280–296 1994

  • 12.

    Hillbom MErila TSotaniemi Ket al: Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study. Acta Neurol Scand 106:84922002Hillbom M Erila T Sotaniemi K et al: Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized double-blind study. Acta Neurol Scand 106:84–92 2002

  • 13.

    Hillman JFridriksson SNilsson Oet al: Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 97:7717782002Hillman J Fridriksson S Nilsson O et al: Immediate administration of tranexamic acid and reduced incidence of early rebleeding after aneurysmal subarachnoid hemorrhage: a prospective randomized study. J Neurosurg 97:771–778 2002

  • 14.

    Hop JWRinkel GJAlgra Aet al: Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:6606641997Hop JW Rinkel GJ Algra A et al: Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 28:660–664 1997

  • 15.

    Hoppensteadt DAWalenga JMFasanella Aet al: TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and a low molecular weight heparin. Thromb Res 77:1751851995Hoppensteadt DA Walenga JM Fasanella A et al: TFPI antigen levels in normal human volunteers after intravenous and subcutaneous administration of unfractionated heparin and a low molecular weight heparin. Thromb Res 77:175–185 1995

  • 16.

    Jennett BBond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:4804841975Jennett B Bond M: Assessment of outcome after severe brain damage. A practical scale. Lancet 1:480–484 1975

  • 17.

    Juvela S: Alcohol consumption as a risk factor for poor outcome after aneurysmal subarachnoid haemorrhage. Br Med J 304:166316671992Juvela S: Alcohol consumption as a risk factor for poor outcome after aneurysmal subarachnoid haemorrhage. Br Med J 304:1663–1667 1992

  • 18.

    Juvela SKaste MHillbom M: Effect of nimodipine on platelet function in patients with subarachnoid hemorrhage. Stroke 21:128312881990Juvela S Kaste M Hillbom M: Effect of nimodipine on platelet function in patients with subarachnoid hemorrhage. Stroke 21:1283–1288 1990

  • 19.

    Kay RWong KSYu YLet al: Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 333:158815931995Kay R Wong KS Yu YL et al: Low-molecular-weight heparin for the treatment of acute ischemic stroke. N Engl J Med 333:1588–1593 1995

  • 20.

    Lanzino GKassell NF: Double-blind, randomized, vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America. J Neurosurg 90:101810241999Lanzino G Kassell NF: Double-blind randomized vehicle-controlled study of high-dose tirilazad mesylate in women with aneurysmal subarachnoid hemorrhage. Part II. A cooperative study in North America. J Neurosurg 90:1018–1024 1999

  • 21.

    Macdonald RL: Cerebral vasospasm. Neurosurg Q 5:73971995Macdonald RL: Cerebral vasospasm. Neurosurg Q 5:73–97 1995

  • 22.

    Mary VWahl FUzan Aet al: Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity. Stroke 32:9939992001Mary V Wahl F Uzan A et al: Enoxaparin in experimental stroke: neuroprotection and therapeutic window of opportunity. Stroke 32:993–999 2001

  • 23.

    Nina PSchisano GChiappetta Fet al: A study of blood coagulation and fibrinolytic system in spontaneous subarachnoid hemorrhage. Correlation with hunt-hess grade and outcome. Surg Neurol 55:1972032001Nina P Schisano G Chiappetta F et al: A study of blood coagulation and fibrinolytic system in spontaneous subarachnoid hemorrhage. Correlation with hunt-hess grade and outcome. Surg Neurol 55:197–203 2001

  • 24.

    Nurmohamed MTvan Riel AMHenkens CMet al: Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery. Thromb Haemost 75:2332381996Nurmohamed MT van Riel AM Henkens CM et al: Low molecular weight heparin and compression stockings in the prevention of venous thromboembolism in neurosurgery. Thromb Haemost 75:233–238 1996

  • 25.

    Ohman JHeiskanen O: Timing of operation for ruptured supratentorial aneurysms: a prospective randomized study. J Neurosurg 70:55601989Ohman J Heiskanen O: Timing of operation for ruptured supratentorial aneurysms: a prospective randomized study. J Neurosurg 70:55–60 1989

  • 26.

    Peltonen SJuvela SKaste Met al: Hemostasis and fibrinolysis activation after subarachnoid hemorrhage. J Neurosurg 87:2072141997Peltonen S Juvela S Kaste M et al: Hemostasis and fibrinolysis activation after subarachnoid hemorrhage. J Neurosurg 87:207–214 1997

  • 27.

    The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators: Low molecular weight heparinoid, ORG 10172 (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 279:126512721998The Publications Committee for the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) Investigators: Low molecular weight heparinoid ORG 10172 (danaparoid) and outcome after acute ischemic stroke: a randomized controlled trial. JAMA 279:1265–1272 1998

  • 28.

    Samama MMCohen ATDarmon JYet al: A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 341:7938001999Samama MM Cohen AT Darmon JY et al: A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 341:793–800 1999

  • 29.

    Shaw MDVermeulen MMurray GDet al: Efficacy and safety of the endothelin, receptor antagonist TAK-044 in treating subarachnoid hemorrhage: a report by the Steering Committee on behalf of the UK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Group. J Neurosurg 93:9929972000Shaw MD Vermeulen M Murray GD et al: Efficacy and safety of the endothelin receptor antagonist TAK-044 in treating subarachnoid hemorrhage: a report by the Steering Committee on behalf of the UK/Netherlands/Eire TAK-044 Subarachnoid Haemorrhage Study Group. J Neurosurg 93:992–997 2000

  • 30.

    Shimoda MTakeuchi MTominaga Jet al: Asymptomatic versus symptomatic infarcts from vasospasm in patients with subarachnoid hemorrhage: serial magnetic resonance imaging. Neurosurgery 49:134113502001Shimoda M Takeuchi M Tominaga J et al: Asymptomatic versus symptomatic infarcts from vasospasm in patients with subarachnoid hemorrhage: serial magnetic resonance imaging. Neurosurgery 49:1341–1350 2001

  • 31.

    Tapaninaho A: Deep vein thrombosis after aneurysm surgery. Acta Neurochir 74:18201985Tapaninaho A: Deep vein thrombosis after aneurysm surgery. Acta Neurochir 74:18–20 1985

  • 32.

    Teasdale GMDrake CGHunt Wet al: A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 51:14571988Teasdale GM Drake CG Hunt W et al: A universal subarachnoid hemorrhage scale: report of a committee of the World Federation of Neurosurgical Societies. J Neurol Neurosurg Psychiatry 51:1457 1988

  • 33.

    Weir B: The pathophysiology of cerebral vasospasm. Br J Neurosurg 9:3753901995Weir B: The pathophysiology of cerebral vasospasm. Br J Neurosurg 9:375–390 1995

  • 34.

    Wong GCGiugliano RPAntman EM: Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. JAMA 289:3313422003Wong GC Giugliano RP Antman EM: Use of low-molecular-weight heparins in the management of acute coronary artery syndromes and percutaneous coronary intervention. JAMA 289:331–342 2003

TrendMD

Metrics

Metrics

All Time Past Year Past 30 Days
Abstract Views 100 100 18
Full Text Views 123 123 0
PDF Downloads 112 112 1
EPUB Downloads 0 0 0

PubMed

Google Scholar