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ORIGINAL ARTICLE
Year : 2019  |  Volume : 67  |  Issue : 5  |  Page : 1286-1289

Ozagrel for Postoperative Management of Aneurysmal Subarachnoid Hemorrhages


Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication19-Nov-2019

Correspondence Address:
Dr. Dhananjaya I Bhat
Department of Neurosurgery, National Institute of Mental Health and Neurosciences, Bengaluru - 560 029, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.271236

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 » Abstract 


Background: A number of pharmacological agents have been tried to circumvent the problem of delayed cerebral ischemia (DCI) with ozagrel sodium being one such agent aimed at the prevention of DCI. Ozagrel is an inhibitor of thromboxane synthetase. It has anti-platelet aggregation action and it dilates vessels. Ozagrel was not available outside Japan till recently. It is available now in India and we had the opportunity to use it among patients with aneurysmal subarachnoid hemorrhage (SAH).
Aims: To analyse the results of ozagrel administration for patients with aneurysmal SAH.
Settings and Design: Tertiary care neurosurgical center.
Materials and Methods: Retrospective analysis of the outcomes of patients who received ozagrel after microsurgical cllipping of aneurysm and comparison with a control grpup who received treatment as usual.
Statistical Analysis: The t-test (two-tailed), Chi-square test, and Mann–Whitney U-test asymptomatic significance (two-tailed), were used respectively for continuous, categorical, and ordinal variables. The significance was determined at P = 0.05 level.
Results: A total of 106 patients underwent surgical clipping of their ruptured intracranial aneurysms over a period of 22 months. Forty two (39.6%) patients received ozagrel, and 62 (60.4%) received the standard treatment. Ozagrel was started at a median of one [interquartile range (IQR) 0.75] day after the surgery, and was given for a median of five (IQR 5) days after the surgery. There was no difference in age, postictal days, World Federation Neurosurgical Society grade, Fisher grade, and the size of ruptured aneurysm in patients who received ozagrel compared to the patients who did not receive ozagrel. Of the 42 patients who received ozagrel, 30 patients (71.4%) had preoperative angiographic vasospasm which improved after the administration of ozagrel. Fifteen (35.5%) patients who received ozagrel developed delayed cerebral ischemia compared to only 11 (17.2%) patients who did not receive ozagrel. Thirty-six (85.7%) patients who received ozagrel had favorable outcome at discharge compared to 52 (81.3%) patients who did not receive ozagrel. No adverse event was observed with ozagrel therapy. At 3-month follow-up, 37 patients (88.1%) who received ozagrel had favorable outcomes against 53 patients (82.8%) who did not receive ozagrel.
Conclusion: Ozagrel may be a useful drug in the armamentarium to treat vasospasm after aneurysmal SAH. A future multicenter large cohort study may validate the findings of our study.


Keywords: Cerebral aneurysm, ozagrel, subarachnoid hemorrhage, thromboxane A2, vasospasm
Key Message: The use of ozagrel may be beneficial in the management of vasospasm and the improve the clinical outcome after aneurysmal subarachnoid hemorrhage.


How to cite this article:
Narayan V, Shukla D, Bhat DI, Prabhuraj A R, Devi BI. Ozagrel for Postoperative Management of Aneurysmal Subarachnoid Hemorrhages. Neurol India 2019;67:1286-9

How to cite this URL:
Narayan V, Shukla D, Bhat DI, Prabhuraj A R, Devi BI. Ozagrel for Postoperative Management of Aneurysmal Subarachnoid Hemorrhages. Neurol India [serial online] 2019 [cited 2019 Dec 7];67:1286-9. Available from: http://www.neurologyindia.com/text.asp?2019/67/5/1286/271236




Aneurysmal subarachnoid hemorrhage (SAH) is one of the most devastating forms of stroke with significant morbidity and mortality worldwide.[1] The development of cerebral vasospasm and delayed cerebral ischemia (DCI) is an important cause of neurological deterioration and death in patients with SAH. In addition to macrovascular spasm, the pathogenesis of DCI is thought to be related to processes such as smooth muscle contraction, endothelial damage, hyperviscosity, apoptosis of endothelial cells and neurons, cerebral edema, loss of blood–brain barrier, abnormal cerebral autoregulation, microthrombosis, cortical spreading depolarization, and inflammation.[1] A number of pharmacological agents have been tried to circumvent the problem of DCI, with ozagrel sodium being one of them.[1],[2]

Ozagrel sodium is 3-[4-(1H-imidazol-1-ylmethyl) phenyl]-2E-propenoic acid; OKY-046. It is an inhibitor of thromboxane synthetase resulting in the decreased production of thromboxane A2 (TXA2). Ozagrel has antiplatelet aggregation action and can dilate vessels. It inhibits vasospasm, increases blood flow quantity, improves microcirculation and energy metabolism, and thereby reduces cerebral ischemia after SAH and thrombotic strokes.[3] Hence, theoretically, the drug may improve the outcome of patients with SAH associated with vasospasm. The main adverse effect of ozagrel is bleeding; thus when used with platelets or anticoagulants, the incidence of hemorrhage may increase.[4] A double-blind study was conducted at 48 neurosurgical services in Japan to investigate the usefulness of OKY-046.[5] The occurrence of cerebral vasospasm and development of low density area in computerized tomography (CT) scans was significantly lower in OKY-046 group compared to placebo. Improvement in motor paralysis and functional outcome at one month was significantly better in OKY-046 group compared to placebo. OKY-046 was found clinically useful at a dose of 80 mg/d for cerebral vasospasm and cerebral ischemic symptoms after aneurysmal SAH.[5] Ozagrel is also used to treat atherothrombotic strokes in Japan. It is the most common drug used to treat lacunar infarcts.[6] Intravenous administration of ozagrel is recommended within five days after onset in noncardioembolic stroke according to Japanese guidelines for the management of stroke.[7]

However, the use of ozagrel was restricted to Japan due to the nonavailability of the same outside Japan. Since ozagrel became available in the last few years in our country, we have started using it for patients with SAH. Here, we report our experience with the use of ozagrel in aneurysmal SAH patients.


 » Materials and Methods Top


This is a retrospective review of consecutive patients who underwent aneurysm clipping followed by ozagrel administration in addition to standard SAH medical management in a single neurosurgical unit. The clinical, imaging, and outcome data of aneurysmal SAH patients managed surgically during the period of January 2014 to October 2015 was collected and analyzed. The patients who underwent endovascular management and clipping for unruptured aneurysms were excluded from the study. The standard postoperative care was the maintainence of normotension or permissive hypertension, normovoelmia, prophylactic anticonvulsant for one week, correction of dyselectrolytemia, if any, treatment of hydrocephalus, if present, and oral nimodipine, a calcium channel blocker, at a dose of 60 mg every fourth hour for 21 days. Ozagrel was administered at a dose of 80 mg/day as a continuous intravenous infusion after surgery for some patients. It was continued until improvement or discharge, death, or for a maximum of 14 days. The patients who were discharged early were advised to complete the 14-day ozagrel treatment in a general hospital. The effect of ozagrel on the development of DCI and condition at discharge was determined. In a single neurosurgical unit, one of the surgeons (DS) preferred to start ozagrel after clipping of the aneurysm in patients with preoperative angiographic vasospasm. Any decline in neurological status on clinical examination including alertness, motor, and speech deficits without other identifiable causes such as hydrocephalus, hyponatremia, seizure, intracranial hematoma, or infection was used to define the presence of DCI.[8] Patients with DCI were then managed with intra-arterial nimodipine therapy. For the purpose of this study, the favorable outcome at discharge was defined as the recovery of neurological deficits or no neurological deficits and mild disability, i.e. monoplegia or hemiparesis or paraparesis with a motor power of ≥3/5. The unfavorable outcome included severe disability, i.e., hemiplegia, or paraplegia with motor power <3/5, altered sensorium, and death. At three months of follow-up, the patients were assessed and the Glasgow outcome scale (GOS) was calculated.[9]

Statistical analysis

The data was entered and analysed in SPSS 20 (SPSS Inc., Chicago, USA). The values were expressed as mean ± standard deviation (SD) for continuous variables, median with first interquartile range (IQR) for ordinal variables, and numbers with percentages for categorical variables. The t-test (two-tailed), Chi-square test, and Mann–Whitney U-test asymptomatic significance (two-tailed), were used respectively for continuous, categorical, and ordinal variables, respectively. The significance was determined at P = 0.05 level.


 » Results Top


A total of 106 patients underwent surgical clipping of ruptured intracranial aneurysma. All ruptured aneurysms were clipped and secured. There were no rebleeds. There were no neck remnants. Forty-two (39.6%) patients received ozagrel, and 62 (60.4%) received standard treatment, as already detailed. Most of the patients were females and in the sixth decade of life. Most of the patients were in good World Federation Neurosurgical Society (WFNS) grade and poor Fischer CT grade. The majority of the patients had small-sized aneurysms. Ozagrel was started at a median of one, (IQR 0.75) day after the surgery and was given for median of 5 (IQR 5) days after surgery. There was no difference in age, postictal days, WFNS grade, Fisher grade, and size of ruptured aneurysm in patients who received ozagrel compared to patients who did not receive ozagrel. However, preoperative angiographic vasospasm was seen in 30 (71.4%) patients who received ozagrel compared to 21 (32.8%) patients who did not receive ozagrel. This difference was statistically significant (P < 0.001) [Table 1]. None of the patients who received ozagrel developed new-onset intracranial hemorrhage. Fifteen (35.5%) patients who received ozagrel developed DCI compared to only 11 (17.2%) patients who did not receive ozagrel; the difference was significant (P = 0.030). Thirty-six (85.7%) patients who received ozagrel had a favorable outcome at discharge compared to 52 (81.3%) patients who did not receive ozagrel (P = 0.549). Ninety-nine patients were followed up for a mean of three months (range 1–6). Seven patients died during the hospital stay after clipping of the aneurysm due to severe vasospasm and consequent cerebral infarct. Thirty-seven (88.1%) patients who received ozagrel had favorable outcome at follow-up of three months compared to 53 (82.8%) patients who did not receive ozagrel [Table 2]. There was no significant difference in outcome at discharge and follow-up between both the groups. A subgroup analysis of patients who had preoperative angiographic vasospasm was also performed. It revealed that significantly more patients (93.3%) who received ozagrel had a favorable outcome compared to only 61.9% patients who did not receive ozagrel [Table 3].
Table 1: Comparison of baseline characteristics of patients

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Table 2: Outcome of patients at discharge and follow-up

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Table 3: Subgroup analysis of 51 patients with preoperative angiographic vasospasm

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 » Discussion Top


We started using ozagrel since its availability in our country in the last few years. This is a nonrandomized pilot study conducted to examine the utility of ozagrel in managing vasospasm. We analyzed the outcome of SAH managed with aneurysmal clipping and postoperative ozagrel therapy.

On comparing the patients who received ozagrel with those who did not, we found that significantly more patients in the ozagrel group had preoperative angiographic vasospasm. However, the outcome at discharge and follow-up was not significantly different among patients who received ozagrel compared to patients who did not receive ozagrel. The randomized trial of OKY-046 reported the superiority of ozagrel by focusing on the significantly decreased incidence of cerebral vasospasm and the development of low density area in computerized tomography in patients who received ozagrel. Moreover, the improvement in motor paralysis and functional outcome at one month was also significantly better in ozagrel group.[5] The similarity in outcome may be due to the fact that patients received ozagrel for a shorter duration compared to the two week treatment in the randomized clinical trial. In addition, a greater number of patients who received oxagrel had preoperative vasospasm.[5] In the subgroup of patients who had preoperative angiographic vasospasm, a statistically significant number of patients had a more favorable outcome. This indicates that ozagrel may be beneficial in improving outcome of patients who have vasospasm.

In another study comprising 24 patients by Tokiyoshi et al., 13 patients received ozagrel at a dose of 1 μg/kg/min for 8 to 14 days. The permanent symptomatic vasospasm was seen in 8% patients who received ozagrel compared to 64% in patients who did not receive ozagrel. The outcome was excellent in 77% patients who received ozagrel compared to 36% patients who did not receive ozagrel. These results indicate that ozagrel was significantly effective in decreasing the occurrence of symptomatic vasospasm and improving the functional outcome in patients with aneurysmal SAH.[10]

Ozagrel has also been tried in combination with fasudil, a calcium antagonist that directly affects intracellular Ca++, and reported in two studies.[2],[11] In the first study, out of 117 patients 57 patients were treated with only ozagrel and 60 patients with a combination therapy of ozagrel and fasudil. The combination therapy was found to be significantly more effective in reducing the incidence of low density areas on CT scans. However, there was no significant difference in the occurrence of symptomatic vasospasm.[11] In another study, 3690 patients received fasudil and 1138 patients received combination therapy of fasudil and ozagrel. There was no significant difference in the incidence of adverse events and clinical outcomes between the two groups. The incidence of symptomatic vasospasm and low density areas on CT scan were lower in the fasudil group than in the combination therapy.[2] Both of these studies showed an equivocal effect of ozagrel for the treatment of aneurysmal SAH and cerebral vasospasm.

The retrospective nature of our study produces limitations. The majority of the patients who received ozagrel had angiographic vasospasm before surgery, which can influence the incidence of DCI and clinical outcome. A double-blind, placebo-controlled randomized control trial is ideal for recommending the use of ozagrel in aneurysmal SAH worldwide, and we are aiming to do the same.


 » Conclusion Top


The outcome following aneurysmal clipping greatly depends on several other factors other than surgical expertise. Cerebral vasospasm is one of the factors that can significantly influence the outcome. Therefore, the management of vasospasm should be targeted at its prevention and aggressive management once it sets in. Though we cannot draw any definite conclusion regarding the use of ozagrel in managing aneurysmal SAH patients, it may be beneficial in those who have evident pretreatment vasospasm and may improve their clinical outcomes. However, a large multicenter cohort study may validate the findings of our study.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

1.
Serrone JC, Maekawa H, Tjahjadi M, Hernesniemi J. Aneurysmal subarachnoid hemorrhage: Pathobiology, current treatment and future directions. Expert Rev Neurother 2015;15:367-80.  Back to cited text no. 1
    
2.
Suzuki Y, Shibuya M, Satoh S, Sugiyama H, Seto M, Takakura K. Safety and efficacy of fasudil monotherapy and fasudil-ozagrel combination therapy in patients with subarachnoid hemorrhage: Sub-analysis of the post-marketing surveillance study. Neurol Med Chir (Tokyo) 2008;48:241-7.  Back to cited text no. 2
    
3.
Kawano T, Ono H, Mori K, Iwayama K, Handa H, Yonekawa Y, et al. Effect of selective thromboxane synthetase inhibitor 0KY-046 on delayed cerebral vasospasm following the ruptured cerebral aneurysm. Shinyaku To Rinsho 1986;35:762-74.  Back to cited text no. 3
    
4.
Kitakawa Y, Ozagrel K, Thromboxane A. Sodium Ozagrel. Nihon Rinsho 2006;64:554-61.  Back to cited text no. 4
    
5.
Suzuki S, Sano K, Handa H, Asano T, Tamura A, Yonekawa Y, et al. Clinical study of OKY-046, a thromboxane synthetase inhibitor, in prevention of cerebral vasospasms and delayed cerebral ischaemic symptoms after subarachnoid haemorrhage due to aneurysmal rupture: A randomized double-blind study. Neurol Res 1989;11:79-88.  Back to cited text no. 5
    
6.
Okada K, Kobayashi S, Japanese Standard Stroke Registry Study (JSSRS) Group. Therapeutic strategy for acute stroke--prologue for an epoch of brain attack-The present state of acute ischemic stroke therapy in Japan. Intern Med 2005;44:365-8.  Back to cited text no. 6
    
7.
Shinohara Y, Yamaguchi T. Outline of the Japanese Guidelines for the Management of Stroke 2004 and subsequent revision. Int J Stroke 2008;3:55-62.  Back to cited text no. 7
    
8.
Vergouwen MD, Vermeulen M, van Gijn J, Rinkel GJ, Wijdicks EF, Muizelaar JP, et al. 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;41:2391-5.  Back to cited text no. 8
    
9.
Jennet B, Bond M. Assessment of outcome after severe brain damage. Lancet 1975;1:480-4.  Back to cited text no. 9
    
10.
Tokiyoshi K, Ohnishi T, Nii Y. Efficacy and toxicity of thromboxane synthetase inhibitor for cerebral vasospasm after subarachnoid hemorrhage. Surg Neurol 1991;36:112-8.  Back to cited text no. 10
    
11.
Nakashima S, Tabuchi K, Shimokawa S, Fukuyama K, Mineta T, Abe M. Combination Therapy of Fasudil Hydrochloride and Ozagrel Sodium for Cerebral Vasospasm Following Aneurysmal Subarachnoid Hemorrhage. Neurol Med Chir (Tokyo) 1998;38:805-10.  Back to cited text no. 11
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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