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Anticoagulants for Acute Ischemic StrokeResponse FREE TO VIEW

Mei-Chiun Tseng, PhD; Peter Sandercock, MD; Carl Counsell, MD
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Affiliations: National Sun Yat-Sen University, Kaohsiung, Taiwan,  Department of Clinical Neurosciences, Western General Hospital, Edinburgh,UK,  Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, UK,  Washington Hospital Center, Washington, DC,  Inova Health System, Falls Church, VA,  Uniformed Services University of Health Sciences, Bethesda, MD

Correspondence to: Mei-Chiun Tseng, PhD, Department of Business Management, National Sun Yat-Sen University, Kaohsiung 80424, Taiwan; e-mail: mctseng@mail.nsysu.edu.tw



Chest. 2008;134(2):466-467. doi:10.1378/chest.08-0741
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The metaanalysis by Shorr and colleagues1warrants further discussion. Firstly, the authors do not take into account in their conclusions that—compared with placebo—no anticoagulant regimen has been shown to be safe in terms of hemorrhage in acute ischemic stroke.2 Furthermore, the confidence intervals for their analyses do not rule out significant harm with regards to intracranial and extracranial hemorrhage.

We also had some uncertainties on the detail of how their estimates were calculated. The authors1 considered the total number of patients in the trial of Hillbom et al3to be 148, the trial of Diener et al4to be 545, and the trial of Sherman et al5 to be 1,335. We are concerned that in two trials (Hillbom and Sherman), the number of patients evaluated for efficacy was not the same as that for safety or intention-to-treat population. A note in this regard would be helpful to readers.

The authors1 reported that the incidence of pulmonary embolism in the three study trials was 0.9%. Given a total of 2,028 patients included in their metaanalysis, there would be about 18 patients with this event. However, it seems to us that data (low-molecular-weight heparin vs unfractionated heparin) for pulmonary embolism in the trial of Hillbom et al3were 1/76 vs 3/72, in the trial of Diener et al4were 0/272 vs 1/273, and in the trial of Sherman et al5 were 1/666 vs 6/669. However, we are unable to replicate the odds ratio (OR) for the trial of Diener et al,4 and we are not sure of the total number of events of pulmonary embolism.

The data used for calculating ORs for the outcome of safety also puzzled us. The authors1 reported that intracerebral bleeding occurred in 16 patients. It seems to us that data for the trials of Hillbom et al,3Diener et al,4and Sherman et al5 for this outcome were 1/76 vs 0/72, 2/272 vs 3/273, and 4/877 vs 6/872, respectively. But, we cannot replicate the OR for the trial of Hillbom et al.3 We think the continuity correction for sparse tables, if used, should have been reported, since this information is important for calculating ORs. And for this outcome, the number of patients in the trial of Sherman et al5 is not 1,335. Overall, we think that in order to make the analysis more transparent to readers, the raw data need to be reported, and the time horizon for each outcome (during treatment period or at the end of follow-up) needs to be specified.

The authors have no conflicts of interest to disclose.

The authors have no conflicts of interest to disclose.

Shorr, AF, Jackson, WL, Sherner, JH, et al (2008) Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis.Chest133,149-155. [PubMed] [CrossRef]
 
Gubitz, G, Sandercock, P, Counsell, C Anticoagulants for acute ischaemic stroke. Cochrane Database of Systematic Reviews. 2004; ;Issue 3
 
Hillbom, M, Erilä, T, Sotaniemi, K, et al Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study.Acta Neurol Scand2002;106,84-92. [PubMed]
 
Diener, HC, Ringelstein, EB, von Kummer, R, et al Prophylaxis of thrombotic and embolic events in acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial.Stroke2006;37,139-144. [PubMed]
 
Sherman, DG, Albers, GW, Bladin, C, et al The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison.Lancet2007;369,1347-1355. [PubMed]
 
To the Editor:

Tseng and colleagues1raise several concerns regarding our recent metaanalysis2comparing low-molecular-weight heparin (LMWH) to unfractionated heparin (UFH) for thromboprophylaxis following ischemic stroke. First, we concur with their comment that perhaps no anticoagulant exposure most effectively limits the risk for hemorrhagic transformation following ischemic stroke. Nevertheless, it should be noted that the authors’ own cited review3 examined use of anticoagulants as therapy for acute ischemic stroke, not as prophylaxis against venous thromboembolism (VTE), and they concluded that “people treated with anticoagulants had less chance of developing deep vein thrombosis and pulmonary embolism (PE) following their stroke.”3 We are not aware of any randomized controlled trial that suggests an increased risk of bleeding in patients who receive pharmacologic VTE prophylaxis. Additionally, the question regarding how much certainty one needs regarding the likelihood that an adverse event does not occur must be examined both statistically and clinically; in other words, for serious events one often requires a high degree of certainty in order to conclude that some intervention is “safe.” Of course, clinicians must weigh risks against benefits and consider the potential for VTE, which may be common following stroke in the absence of pharmacologic prophylaxis and which is a challenge to treat in such subjects.

Second, we acknowledge the described inversion error and agree that the 0.9% rate for PE should be 0.6%. Third, we believe some of the differences in the crude odds ratios (ORs) they describe arise because of issues with how to adjust statistically for event rates that fail to occur in one arm of a trial. When a cell is left as a zero for a numerator in an OR calculation, mathematically, specific computation of the OR ratio may be imprecise.

Fourth, extracting data from tables in various studies in order to conduct metaanalysis may not necessarily be straightforward. There is often room for interpretation, and that is why we had two separate authors complete the data abstraction. Nonetheless, we admit that other readers may have viewed the primary data differently.

Finally, and most importantly, even if one accepts the data values provided by Tseng and coworkers,1 our conclusions remain unchanged. Employing the information provided in their letter and utilizing a random-effects model (without adjusting for zero cells), the pooled OR for pulmonary embolism with LMWH vs UFH is 0.24 (95% confidence interval [CI], 0.06 to 0.97; p = 0.045). This is not meaningfully different from the result we reached and reported in the article (OR, 0.26; 95% CI, 0.07 to 0.95; p = 0.042). Similarly, relying on their inputs for intracerebral hemorrhage and utilizing a random-effects model yields an OR of 0.76 favoring LMWH, and the 95% CI ranges from 0.28 to 2.04 (p = 0.588), again nearly identical to our point estimate. Calculating the pooled OR for intracerebral hemorrhage with a fixed-effects model and their data also results in observations essentially indistinguishable from our own. Their work thus, in part, helps verify our results and conclusions, and demonstrates that our overall findings do not seem altered if an entirely distinct cohort of investigators is reviewing the trials.

References
Tseng, MC, Sandercock, P, Counsell, C Anticoagulants for acute ischemic stroke.Chest2008;134,466. [PubMed] [CrossRef]
 
Shorr, AF, Jackson, WL, Sherner, JH, et al Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis.Chest2008;133,149-155. [PubMed]
 
Gubitz, G, Sandercock, P, Counsell, C Anticoagulants for acute ischaemic stroke.Cochrane Database Syst Rev2004;,CD000024
 

Figures

Tables

References

Shorr, AF, Jackson, WL, Sherner, JH, et al (2008) Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis.Chest133,149-155. [PubMed] [CrossRef]
 
Gubitz, G, Sandercock, P, Counsell, C Anticoagulants for acute ischaemic stroke. Cochrane Database of Systematic Reviews. 2004; ;Issue 3
 
Hillbom, M, Erilä, T, Sotaniemi, K, et al Enoxaparin vs heparin for prevention of deep-vein thrombosis in acute ischaemic stroke: a randomized, double-blind study.Acta Neurol Scand2002;106,84-92. [PubMed]
 
Diener, HC, Ringelstein, EB, von Kummer, R, et al Prophylaxis of thrombotic and embolic events in acute ischemic stroke with the low-molecular-weight heparin certoparin: results of the PROTECT Trial.Stroke2006;37,139-144. [PubMed]
 
Sherman, DG, Albers, GW, Bladin, C, et al The efficacy and safety of enoxaparin versus unfractionated heparin for the prevention of venous thromboembolism after acute ischaemic stroke (PREVAIL Study): an open-label randomised comparison.Lancet2007;369,1347-1355. [PubMed]
 
Tseng, MC, Sandercock, P, Counsell, C Anticoagulants for acute ischemic stroke.Chest2008;134,466. [PubMed] [CrossRef]
 
Shorr, AF, Jackson, WL, Sherner, JH, et al Differences between low-molecular-weight and unfractionated heparin for venous thromboembolism prevention following ischemic stroke: a metaanalysis.Chest2008;133,149-155. [PubMed]
 
Gubitz, G, Sandercock, P, Counsell, C Anticoagulants for acute ischaemic stroke.Cochrane Database Syst Rev2004;,CD000024
 
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