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.

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 0.5 and 1.0 mg/kg, 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 i.v. 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 i.v., had less vasospasm and DCI during admission, compared to patients treated with prophylactic LMWH (40 mg s.c.). 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 i.v. 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%, respectively).[26] 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.

Inclusion Criteria:

• 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

Exclusion Criteria:

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

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