Ignite Creation Date:
2024-05-06 @ 3:03 PM
Last Modification Date:
2024-10-26 @ 1:42 PM
Study NCT ID:
NCT04507178
Status:
RECRUITING
Last Update Posted:
2023-07-24
First Post:
2020-08-07
Brief Title:
Improving Outcome in Subarachnoid Hemorrhage wIth Nadroparine
Sponsor:
Academisch Medisch Centrum - Universiteit van Amsterdam AMC-UvA
Organization:
Academisch Medisch Centrum - Universiteit van Amsterdam AMC-UvA
Study Overview
Official Title:
Improving Outcome in Subarachnoid Hemorrhage wIth Nadroparine
Status:
RECRUITING
Status Verified Date:
2023-07
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
ISCHEMIA
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 sc 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 sc 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 ventricularlumbar drain EVDELD 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
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 sc 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 sc 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 ventricularlumbar drain EVDELD 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
Detailed Description:
One in every 20 strokes is caused by aneurysmal subarachnoid hemorrhage aSAH Mortality amounts to 32-39 and 50 of the survivors experience a permanent disability Because half of the patients is younger than 55-years-old the loss of productive life years has an enormous economic and social impact One of the leading causes for morbidity and mortality after aSAH is delayed cerebral ischemia DCI which occurs in 20-40 of the patients
Cerebral vasospasm in reaction to aneurysm wall rupture and subarachnoid blood was long considered to be the principal determinant contributing to DCI This concept has led to routine treatment with nimodipine a calcium channel blocker with only modest success on the prevention of DCI and clinical outcome Growing experimental and clinical evidence shows that not necessarily vasospasm but the activation of several key pathophysiological pathways may be the principal determinant of DCI Cortical spreading depressions endothelial dysfunction procoagulant activity causing microthrombosis neuroinflammation oxidative stress necrosis and apoptosis may all contribute to brain injury after the acute intracranial circulatory arrest of the initial hemorrhage Due to this not fully understood complex pathophysiology many different treatment strategies have been proposed of which none seem sufficient for preventing or treating secondary brain damage
Heparin is a pleiotropic drug which has over 100 discovered heparin-binding proteins Since before 1980 and most recently in 2017 studies have argued the possible beneficial effect of heparin in aSAH patients Before 1995 studies in animals and ex vivo suggested that heparin could relax narrowed vessels improve blood and cerebrospinal fluid flow and prevent proliferative angiopathy and cerebral ischemia Furthermore in ischemic stroke models in rats heparin significantly reduced ischemic damage with a wide therapeutic window In 2011 results in vivo showed that vein injection of Ultra-Low-Molecular-Weight Heparin at doses of 05 and 10 mgkg exerted significant neuroprotective effects in rats with focal cerebral ischemic injury by significantly reducing the infarct volume compared with the injury group In 2012 a SAH model in rats showed that heparin significantly reduced neuroinflammation demyelination and trans synaptic apoptosis Recent studies emphasize the wide-ranging and broad anti-inflammatory and immune-modulatory activities of heparin which are independent of its anticoagulant effects as underlying mechanisms of effect Among others heparin binds oxyhemoglobin blocks the activity of free oxygen radicals antagonizes endothelin-mediated vasoconstriction binds to several cytokines and all chemokines anti-inflammatory and several growth factors antimitogenic and antifibrotic In addition heparin antagonizes the activation of pathways that seem responsible for ischemic brain damage in aSAH patients Henceforth not DCI prevention in itself but rather modulation of several pathophysiological processes could be targeted by heparin-treatment
The only study which investigated the effect of postinterventional continuous iv unfractionated heparin UFH aPTT targeted to 60s for 24 hours up to seven days in endovascularly treated aSAH patients is a recent retrospective study in 394 aSAH patients The interventional neuroradiologist determined whether additional heparinization was necessary and indications included thrombo-embolic prophylaxis especially in the case of a broad aneurysm neck coil dislocation into the carrier vessel or intraprocedural thrombus formation The 197 patients treated with therapeutic UFH iv had less vasospasm and DCI during admission compared to patients treated with prophylactic LMWH 40 mg sc In contrast there was no beneficial ef-fect on outcome after six months follow-up However as patients with therapeutic UFH were only treated for 7 days and DCI continues to develop until 14 days after aneurysm rupture this study presumably underestimated the effect of heparin Additionally it has been shown that in critically ill patients the aPTT is not accurate enough to detect UFH iv with the danger of underdosing and overdosing
Recently a retrospective analysis of 93 aSAH patients treated with therapeutic LMWH nadroparin twice daily 5700 AxaIU subcutaneously until discharge with a median duration of 17 days found a significant difference of in-hospital mortality when compared to 65 patients treated with prophylactic dose LMWH once daily 2850 AxaIU subcutaneously until discharge 5 and 23 respectively26 In addition discharge to home was significantly higher in patients who received therapeutic LMWH compared to low-dose LMWH 40 and 17 respectively
In summary there is evidence that LMWH in a higher dosage is beneficial for the clinical outcome of endovascularly treated aSAH patients Treatment with higher dose LMWH might significantly reduce 30 days mortality The aim of this study is to reproduce this beneficial effect of therapeutic LMWH in a randomized controlled trial Improving outcome in SubaraChnoid HEMorrhage wIth NAdroparin ISCHEMIA-study The ISCHEMIA-study challenges existing treatment paradigms which are mostly aimed at blood-induced vasospasm and will be the first randomized controlled trial RCT to investigate the effect of higher dose LMWH in aSAH patients
Cerebral vasospasm in reaction to aneurysm wall rupture and subarachnoid blood was long considered to be the principal determinant contributing to DCI This concept has led to routine treatment with nimodipine a calcium channel blocker with only modest success on the prevention of DCI and clinical outcome Growing experimental and clinical evidence shows that not necessarily vasospasm but the activation of several key pathophysiological pathways may be the principal determinant of DCI Cortical spreading depressions endothelial dysfunction procoagulant activity causing microthrombosis neuroinflammation oxidative stress necrosis and apoptosis may all contribute to brain injury after the acute intracranial circulatory arrest of the initial hemorrhage Due to this not fully understood complex pathophysiology many different treatment strategies have been proposed of which none seem sufficient for preventing or treating secondary brain damage
Heparin is a pleiotropic drug which has over 100 discovered heparin-binding proteins Since before 1980 and most recently in 2017 studies have argued the possible beneficial effect of heparin in aSAH patients Before 1995 studies in animals and ex vivo suggested that heparin could relax narrowed vessels improve blood and cerebrospinal fluid flow and prevent proliferative angiopathy and cerebral ischemia Furthermore in ischemic stroke models in rats heparin significantly reduced ischemic damage with a wide therapeutic window In 2011 results in vivo showed that vein injection of Ultra-Low-Molecular-Weight Heparin at doses of 05 and 10 mgkg exerted significant neuroprotective effects in rats with focal cerebral ischemic injury by significantly reducing the infarct volume compared with the injury group In 2012 a SAH model in rats showed that heparin significantly reduced neuroinflammation demyelination and trans synaptic apoptosis Recent studies emphasize the wide-ranging and broad anti-inflammatory and immune-modulatory activities of heparin which are independent of its anticoagulant effects as underlying mechanisms of effect Among others heparin binds oxyhemoglobin blocks the activity of free oxygen radicals antagonizes endothelin-mediated vasoconstriction binds to several cytokines and all chemokines anti-inflammatory and several growth factors antimitogenic and antifibrotic In addition heparin antagonizes the activation of pathways that seem responsible for ischemic brain damage in aSAH patients Henceforth not DCI prevention in itself but rather modulation of several pathophysiological processes could be targeted by heparin-treatment
The only study which investigated the effect of postinterventional continuous iv unfractionated heparin UFH aPTT targeted to 60s for 24 hours up to seven days in endovascularly treated aSAH patients is a recent retrospective study in 394 aSAH patients The interventional neuroradiologist determined whether additional heparinization was necessary and indications included thrombo-embolic prophylaxis especially in the case of a broad aneurysm neck coil dislocation into the carrier vessel or intraprocedural thrombus formation The 197 patients treated with therapeutic UFH iv had less vasospasm and DCI during admission compared to patients treated with prophylactic LMWH 40 mg sc In contrast there was no beneficial ef-fect on outcome after six months follow-up However as patients with therapeutic UFH were only treated for 7 days and DCI continues to develop until 14 days after aneurysm rupture this study presumably underestimated the effect of heparin Additionally it has been shown that in critically ill patients the aPTT is not accurate enough to detect UFH iv with the danger of underdosing and overdosing
Recently a retrospective analysis of 93 aSAH patients treated with therapeutic LMWH nadroparin twice daily 5700 AxaIU subcutaneously until discharge with a median duration of 17 days found a significant difference of in-hospital mortality when compared to 65 patients treated with prophylactic dose LMWH once daily 2850 AxaIU subcutaneously until discharge 5 and 23 respectively26 In addition discharge to home was significantly higher in patients who received therapeutic LMWH compared to low-dose LMWH 40 and 17 respectively
In summary there is evidence that LMWH in a higher dosage is beneficial for the clinical outcome of endovascularly treated aSAH patients Treatment with higher dose LMWH might significantly reduce 30 days mortality The aim of this study is to reproduce this beneficial effect of therapeutic LMWH in a randomized controlled trial Improving outcome in SubaraChnoid HEMorrhage wIth NAdroparin ISCHEMIA-study The ISCHEMIA-study challenges existing treatment paradigms which are mostly aimed at blood-induced vasospasm and will be the first randomized controlled trial RCT to investigate the effect of higher dose LMWH in aSAH patients
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
False
Is a FDA Regulated Device?:
False
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None