Aspirin Versus Low-Molecular-Weight Heparin for Ischemic Stroke in Children: An Unanswered Question
To the Editor:
We read with interest the article entitled “Aspirin Versus Low-Dose Low-Molecular-Weight Heparin: Antithrombotic Therapy in Pediatric Ischemic Stroke Patients: A Prospective Follow-Up Study.”1 As addressed by the authors, there is scant evidence to guide the treatment of children with stroke. Thus, the authors have contributed important and significant knowledge regarding the treatment of pediatric stroke. This includes valuable information on the safety and feasibility of administering aspirin or low-molecular-weight heparin (LMWH) in a large number of children with stroke. However, the design and results of the present study cannot substantiate the following conclusion: “This prospective multicenter follow-up study has provided evidence that low-dose LMWH is not superior to aspirin and vice versa in preventing recurrent stroke ….” Because the treatment was assigned by multiple treating physicians and was not prospectively standardized, it is possible that patients deemed to have an increased risk of recurrence were treated with LMWH and low-risk patients were treated with aspirin (or vice versa). Although these shortcomings are addressed in the article, they are not reflected in the conclusions.
Readers should be aware of the fact that low-dose LMWH (at “prophylactic” doses) was used in the study, as has been clearly stated by the authors. Therapeutic doses of LMWH may prevent stroke recurrence in children, as has been shown in adults with stroke,2 but without the risks of hemorrhagic complications seen in adults. This is because in children there is a lack of hypertension, atherosclerosis, and other age-related factors known to increase the risk of hemorrhagic complications. In our institutional consecutive cohort studies, 81 infants and children with arterial strokes have received therapeutic LMWH for initial treatment of arterial stroke, and there were no major bleeding complications (Dix et al3 and W. Ng, MHSc, et al, unpublished data, 2002).
A randomized, controlled trial is the appropriate trial design for assessing efficacy in prevention of stroke. Given the risk of recurrent arterial stroke or transient ischemic attacks in children of up to 45%,4 a trial assessing aspirin and other alternative treatments is both timely and necessary in children with stroke. Multicenter studies, such as Strater and colleagues have conducted, are critical to the feasibility of such trials.
In summary, we suggest that the conclusion in the article remains a speculation and that insufficient evidence has been provided to conclude that aspirin and low-dose LMWH are equivalent in the prevention of pediatric stroke.
- ↵Strater R, Kurnik K, Heller C, Schobess R, Luigs PM, Nowak-Gottl U, for the Childhood Stroke Study Group. Aspirin versus low-molecular-weight heparin: antithrombotic therapy in pediatric ischemic stroke patients: a prospective follow-up study. Stroke. 2001; 32: 2554–2558.
- ↵Gubitz G, Counsell C, Sandercock P, Signorini D. Anticoagulants for acute ischaemic stroke (Cochrane review). In: The Cochrane Library, issue 4, 2000. Oxford, UK: Update Software.
- ↵Askalan R, Laughlin S, Mayank S, Chan A, MacGregor D, Andrew M, Curtis R, Meaney B, deVeber G. Chickenpox and stroke in childhood: a study of frequency and causation. Stroke. 2001; 32: 1257–1262.
We wish to thank our colleagues deVeber and Chan for their letter, discussing our data on secondary prevention of recurrence after childhood stroke. In their comments on our article, deVeber and Chan raised important issues.
The first issue relates to our conclusion, “This prospective multicenter follow-up study has provided evidence that low-dose LMWH is not superior to low-dose aspirin and vice versa in preventing recurrent stroke in white pediatric stroke patients.”1 The treatment options used in our study are only 2 chosen from a wide spectrum of possibilities. Only prophylactic dosage regimens were used in this survey, and aspirin and low-molecular-weight heparin (LMHW) seemed to be similarly effective without major side effects. We therefore completely agree with deVeber and Chan that because treatment modalities were assigned by multiple physicians and therapy was not prospectively standardized, the possibility that children deemed to have an increased risk were treated with LMWH and children with a lower risk for a second stroke were treated with aspirin or vice versa must be discussed. Despite the nonrandomization, discussed as a limitation in the present article, for the white German stroke patients treated in our study, we have shown that there was no statistical difference with respect to age, vascular territory involved, or presence of inherited thrombophilia in the 2 treatment arms. We have additionally discussed that our findings that no significant difference was observed between low-dose aspirin and low-dose LMWH with respect to stroke recurrence were based on a nonrandomized intervention or decision or choice of treatment modalities and therefore have the potential for considerable bias. The latter fact was clearly pointed out in the Discussion as a further limitation of the study. In addition, the conclusions drawn from the present cohort study, with all the limitations mentioned in the article, apply only to the German children treated here and are not transferable to stroke children of other countries or other ethnic populations. Thus, we kindly acknowledge that deVeber and Chan clarified this important issue.
The second issue relates to the dosage used for LMWH. The patients treated by us did not receive high doses of LMWH even in the acute phase of stroke onset, mainly because no safety data are available. Thus, the only possibility for us was to use a low-dose LMWH regimen as one drug for secondary long-term stroke prophylaxis. In addition, in contrast to the Canadian pediatric population, the majority of German children suffering from ischemic stroke or venous thromboembolic events received LMWH as a secondary prophylactic treatment beyond the acute thromboembolic onset in a low-dose regimen administered once daily only. This regimen beyond the acute phase in the cohort presented here was safe, without any bleeding complications within the entire study period. This may not be true for high-dose LMWH, however.2 In this prospective follow-up study including 29 children with ischemic stroke and an additional cohort with venous thrombosis, the event-free survival was no different between high- and low-dose LMWH.2 On the other hand, major bleeding complications were observed in 5% of patients in the high-dose LMWH group, including 1 intracerebral hemorrhage into an old ischemic stroke area in a child suffering from congenital heart disease. No such complication was mentioned for children treated with low-dose LMWH.2 It is therefore possible that major bleeding complications are more common in children treated with higher doses of LMWH, eg, 1.5 mg/kg every 12 hours.2,3⇓ In the unpublished data cited by the authors, which was kindly offered to us by deVeber before publication (W. Ng, MD, et al, unpublished data, 2002), the Canadian group reports on 51 children who received high-dose LMWH therapeutically for a median of 11 days after acute stroke onset; no major bleeding complication was observed. In our German study, children with a 2-phase initial stroke onset were not included as “second stroke patients,” and recurrent stroke events were diagnosed at a median (range) of 5 (2 to 13) months after first stroke onset with antithrombotic medication still being administered. Interestingly, however, the recurrence rate reported in the Canadian cohort, eg, 1 second stroke event in 51 children (2%) treated with high-dose LMWH, is within the rates (with estimated 95% CIs) reported for recurrent stroke in our cohort (spontaneous stroke, 4.8% [3.7 to 20.2]; cardiac stroke, 10% [0.2 to 44.5]; vascular stroke, 16.7% [20 to 48.4]; infectious stroke, 0% [0 to 45.9]).
Additionally, there are concerns that LMWH is possibly associated with dose-dependent adverse effects, eg, a reduction of bone mineral density, which has been reported in children using long-term warfarin therapy.4 Thus, additional safety data on the short- and long-term use of high- and low-dose LMWH are urgently needed to make a final decision regarding whether LMWH is a candidate for trials of secondary stroke prevention in children.
Stroke types in children differ essentially from those in the elderly,5 and therefore therapeutic guidelines from adult stroke patients are not simply transferable to children. Thus, since there is still scant evidence of stroke treatment in children, we agree with deVeber and Chan that randomized controlled trials in stroke children with an appropriate design, including comparable stroke classifications,6–8⇓⇓ clearly defined study end points based on suitable and comparable imaging methods, and the analysis of underlying prothrombotic risk factors,9 are urgently required on the basis of an International Pediatric Stroke Consensus. Which drugs besides aspirin should be used, however, in the specific pediatric stroke subtypes, eg, high-dose LMWH, low-dose LMWH, or vitamin K antagonists, remains an unanswered question, with the need for more basic pharmacological data obtained in children.
Finally, we again gratefully acknowledge the comments made by deVeber and Chan; they are indeed critical for further stroke studies in children, which we hope will be conducted as multicenter international studies in the near future.
- ↵Straeter R, Kurnik K, Heller C, Schobess R, Luigs P, Nowak-Göttl U, for the Childhood Stroke Study Group. Aspirin versus low-molecular-weight heparin: antithrombotic therapy in pediatric ischaemic stroke patients: a prospective follow-up study. Stroke. 2001; 32: 2554–2558.
- ↵Cheung AM, Halton J, Dinyari M, Chan A, Shaughnessy S, Webber C, Massicotte P. Bone mineral density (BMD) in a cohort of children on long term warfarin therapy (>1 year). Thromb Haemost. 2001; suppl. Abstract OC1729.
- ↵Williams LS, Garg BP, Cohen M, Fleck JD, Biller J. Subtypes of ischemic stroke in children and young adults. Neurology. 1997; 49: 1541-1545.
- ↵Kirkham FJ. Stroke in childhood. Arch Dis Child. 1999; 81: 85–89.
- ↵Mathews KD. Stroke in neonates and children: overview. In: Biller J, Mathews KD, Love BB, eds. Stroke in Children and Young Adults. Boston, Mass: Butterworth-Heinemann; 1994: 15-29.
- ↵Nowak-Göttl U, Sträter R, Heinecke A, Junker R, Koch HG, Schuierer G, von Eckardstein A. Lipoprotein (a) and genetic polymorphisms of clotting factor V, prothrombin, and methylenetetrahydrofolate reductase are risk factors of spontaneous ischaemic stroke in childhood. Blood. 1999; 94: 3678-3682.