• 
• 

Three Part Question

In [children with arterial ischemic stroke (AIS)], does[regular treatment with Aspirin] [reduce the recurrence of strokes]?

Clinical Scenario

You are a paediatric registrar carrying out your shift in paediatric Accident and Emergency. You see a 12 year old girl presenting with an acute onset of right sided stroke. She was admitted to the Children’s ward and on further investigation she was found to have an ischemic stroke involving the left middle cerebral artery territory. Her cardiac evaluation was normal. The Paediatric Neurologist advised commencing her on Aspirin.

The family are anxious about the efficacy and safety of Aspirin. You have heard that Aspirin has been proven to be beneficial in strokes in adults with arterial ischemic infarcts. However, you are not sure if there is enough evidence to justify its use in paediatric age group. You decide to find out the evidence

Search Strategy

Databases: Medline (1950-2011) & Embase (1980-2011) via OVID interface
Keywords: “stroke”, “children”, “Aspirin” AND “Acetyl salicylic acid”

Limits: Human, English

Search Outcome

A total of 246 studies were identified. All the abstracts were read. All studies involving children with pre-existing diseases or conditions (eg. Sickle cell disease, Sturge Weber syndrome, etc) were excluded. One prospective case series and one retrospective and prospective study were included. No randomised trials were available. 12 systematic reviews without metanalysis, guidelines and conference abstracts were excluded.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Strater et al July 2001 Germany	135 consecutively recruited children aged ≥6 months to ≤18 years with a first episode of ischemic stroke received prophylactic antithrombotic therapy aspirin (n= 49, dose: 4 mg/kg body wt per day; range, 2 to 5) or LMWH, n=86, (enoxaparin 1 to 1.5 mg/kg body wt per day or dalteparin 75 to 125 anti-Xa U/kg body wt per day) in a nonrandomized fashion and were prospectively followed up for a median (range) of 36 (8 to 48) months	Prospective follow up study	rate of stroke recurrence	Recurrent ischemic stroke was diagnosed at a median (range) of 5 (2 to 13) months after the first stroke onset in 13 of the 135 children (9.6%) receiving antithrombotic therapy No significant difference in recurrence of stroke was found with respect to the antithrombotic medication used (P=0.76, Fisher’s exact test).	The results obtained from this study are to be interpreted with caution as it involves a small number of subjects enrolled in the respective subgroups. Potential risk of bias exists due to non-randomisation of treatment arms
Ganesan V 2006 United Kingdom	Total of 212 patients were identified with age at first AIS ranged from 21 days to 19.5 years (median 5 years); 115 (54%) were male. 64 of these patients were treated with low-dose aspirin (1mg/kg body weight); 33 patients were given anticoagulation therapy, and 74 received no treatment. Median follow up was 2.2 yrs range (1 day- 21y)	Retrospective and prospective follow up study	rates of and risk factors for clinical and radiological recurrence	One hundred thirty-one children had received treatment to prevent another stroke; 50 of them (38%) had a clinical recurrence, compared with 29 (35%) of 81 who were untreated Prophylactic treatment with aspirin or anticoagulation didn’t significantly influence the incidence of clinical recurrence compared with no prophylaxis, although there was a trend for an effect of aspirin after adjustment for the underlying and vascular diagnoses, (HR, 0.55; 95% CI, 0.26 to 1.16; P 0.11 for aspirin; HR, 1.06; 95% CI, 0.45 to 2.51; P 0.89 for anticoagulation)	97/212 had an underlying diagnosis at presentation; 115/212 previously healthy group. In the previously healthy group, the presence of prothrombotic mutation PT20210 was associated with clinical recurrence (HR 7.89, 95% CI 1.78 to 34.92, P=0.007). The wide confidence interval for some ORs and HRs reflects the numbers in some of the subgroups were small. A potential for referral bias might be important factor behind the higher incidence of recurrence rate.

Comment(s)

Stroke and cerebrovascular disorders are important causes of significant morbidity and mortality in the paediatric population. They are amongst the top 10 causes of childhood death1.The incidence rate for stroke in children is 2–5/100,000 children/year. Stroke is more common in boys than girls and with a peak incidence in the first year of life. Stroke in children has a high recurrence rate and the risk of long term neurological sequela is seen in nearly 50% of survivors. The mortality rate is 20%.1 One of the key aspects in managing stroke in children is the early clinical suspicion, making a prompt definitive diagnosis and investigating for any underlying risk factors. Using appropriate imaging techniques, it is essential to ascertain if it is an ischaemic or haemorrhagic stroke as it will guide further management. Children with haemorrhagic stroke would require an urgent neuro-surgical opinion regarding the need for possible neuro-surgical intervention1 Ischaemic stroke can be arterial or venous in origin. Although ischemic strokes are commonly arterial, cerebral venous sinus thrombosis always needs to be excluded1. Acute treatment of AIS in children is aimed to arrest extension of occlusive thrombosis and prevent early recurrence of stroke. Further management is directed towards prevention of longer-term stroke recurrence. The recurrence risk is higher in the presence of multiple underlying risk factors. Recurrence risk after an episode of stroke is highest in the initial weeks and months and persists for atleast several years14.The five year cumulative recurrence risk of AIS in children is approximately 7 - 20%3. Treatment of stroke in adults is evidence based and NICE guidelines9 are available for the management of stroke in adults. There is evidence to suggest that the use of aspirin in adults with stroke reduces the recurrence rate by approximately 25%7,8 However similar data doesn’t exist for children.14 The purpose of this review is to assess the available evidence for the efficacy and safety of Aspirin in prevention of stroke recurrence in children. Currently there are no randomised controlled trials available that have looked into antithrombotic therapies in children with stroke. We found one prospective case series and one retrospective/ prospective study involving treatment with Aspirin. Ganesan et al10 showed that children on Aspirin prophylaxis showed a trend for fewer recurrences compared with children receiving anticoagulation or no prophylaxis. Strater et al11 showed no difference in recurrence rate of stoke in children treated either with Aspirin or LMWH (P=0.76). No major drug related side effects were observed in 49 children with arterial ischemic stroke when treated with 2 to 5 mg/kg aspirin per day during a median follow-up of 36 months11. Both these studies involved non randomisation of treatment arms leading to potential bias, small number in subgroups and wide statistical ranges (OR’s and CI’s). There are several guidelines available for the management of Paediatric stroke which are largely empirically based on extrapolation of data from studies in adults and consensus among expert opinion2,3. From the large multicentre observational cohort study in children with AIS it is clear that the treatment practice varies widely16. In the UK, the national guideline for the management of stroke was published by Paediatric Stroke Working Group, Royal College of Physicians (RCP) in 2004. The RCP guidelines on acute management of stroke in childhood recommend Aspirin (5 mg/kg) after radiological confirmation of arterial ischaemic stroke6, except in children with Sickle cell disease or evidence of intracranial haemorrhage on imaging6. American Heart Association (AHA) guidelines recommend unfractionated Heparin (UFH) or low molecular weight Heparin (LMWH) (1 mg/kg every 12 h) up to 1 week until the underlying cause is determined10. American College of Chest Physicians guidelines recommends use of UFH or LMWH or aspirin 1–5 mg/kg/day until cardio-embolic and dissection subtypes have been excluded.13 For the secondary preventive management of AIS in children RCP guidelines recommend using Aspirin prophylaxis (1–3 mg/kg/day) once dissection, Moya Moya and Sickle cell disease are excluded6. It recommends the use of anticoagulation if there is recurrence of stroke despite treatment with Aspirin6. American College of Chest Physicians recommends aspirin prophylaxis (1 to 5 mg/kg/d) for a minimum of 2 years and AHA10 mentions a dose of 3-5mg/kg/d for a minimum of 3 -5 years or even longer in the presence of risk factors for recurrent stoke. Data on the safety profile of aspirin in children show that relatively low doses of aspirin used as antithrombotic therapy, compared to the higher doses used for anti-inflammatory treatment rarely cause many side effects.12 However the risks of gastric irritation, worsening of asthma and small risk of Reye’s syndrome persists in these children whilst on prophylaxis with Aspirin. In older children, aspirin rarely causes significant haemorrhage except in the presence of a risk for bleeding tendency. On the basis of currently available evidence, it would be appropriate to say that the treatment with Aspirin appears to be effective in reducing recurrence of arterial ischemic stroke in children. Dosage and duration of treatment with Aspirin has to individualised based on the underlying diagnosis, risk factors and tolerability. We acknowledge that large scale randomised clinical trials will not be easy to undertake in the Paediatric stroke population. However there is definitely a need for multicentre large scale observational cohort studies. Bibliography: 1. Kirkham F, Cerebrovascular disease and stroke; Arch Dis Child 2008; 93:890–898. doi:10.1136/adc.2008.142836 2. Zahuranec DB, Brown DL, Lisabeth LD, et al. Is it time for a large, collaborative study of pediatric stroke, Stroke 2005; 36 3. Stroke in Childhood. Current Paediatrics (1994), 4: 208-215. Kirkham F 4. Stroke and cerebrovascular disorders. Current Opinion in Pediatrics, December 2009, vol./is. 21/6(751-761), 1040-8703 5. Bernard T.J Treatment of childhood arterial ischemic stroke. Annals of Neurology, June 2008, vol./is. 63/6(679-696), 0364-5134 6. Stroke in childhood. Clinical guidelines for diagnosis, management and rehabilitation. Paediatric Stroke Working Group. ROYAL COLLEGE OF PHYSICIANS. November 2004 7. Indications for early aspirin use in acute ischemic stroke: A combined analysis of 40 000 randomized patients from the chinese acute stroke trial and the international stroke trial. On behalf of the CAST and IST collaborative groups. Chen ZM, Sandercock P, Pan HC, Counsell C, Collins R, Liu LS, Xie JX, Warlow C, Peto R.Stroke. 2000;31(6):1240. 8. A comparison of warfarin and aspirin for the prevention of recurrent ischaemic stroke. Mohr J.P. et al.N Eng J Med; 345(20): 1444-51 9. National clinical guideline for stroke; Intercollegiate Stroke Working Party, July 2008 10. Management of Stroke in Infants and Children : A Scientific Statement From the Special Writing Group of the American Heart Association Stroke Council and the Council on Cardiovascular Disease in the Young; Stroke 2008, 39:2644-269 11. Ganesan V et al; Clinical and Radiological Recurrence After Childhood Arterial Ischemic Stroke; Circulation 2006, 114:2170-2177 12. Strater et al; Aspirin Versus Low-Dose Low-Molecular-Weight Heparin: Antithrombotic Therapy in Pediatric Ischemic Stroke Patients : A Prospective Follow-Up Study; Stroke 2001, 32:2554-2558 13. Monagle P; Antithrombotic Therapy in Neonates and Children American College of Chest Physicians Evidence based guidelines; Chest 2008;133;887S-968S 14. De Veber G; Guidelines for the treatment and prevention of stroke in children Reflection and Reaction; the lancet neurology; Vol 7; issue 11; November 2008 15. Bernaud T J; Treatment of Childhood Arterial Ischemic stroke; Ann Neurol 2008;63:679–696 16. Neil A Goldenberg; Antithrombotic treatments, outcomes, and prognostic factors in acute childhood-onset arterial ischaemic stroke: a multicentre, observational, cohort study; Lancet Neurol 2009; 8: 1120–27

Clinical Bottom Line

1. Treatment with Aspirin appears to be effective in reducing recurrence of arterial ischemic stroke in children. (Grade C) 2. Use of low dose Aspirin prophylaxis in arterial ischemic stroke in children appears to be safe, well tolerated and with few side effects.(Grade C) 3. Future multi-centre large scale observational cohort studies would help in consolidating the evidence.

References

1. Strater et al Aspirin Versus Low-Dose Low-Molecular-Weight Heparin: Antithrombotic Therapy in Pediatric Ischemic Stroke Patients : A Prospective Follow-Up Study Stroke 2001, 32:2554-2558
2. Ganesan V et al Clinical and Radiological Recurrence After Childhood Arterial Ischemic Stroke Circulation 2006, 114:2170-2177