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Progress Reviews

Efficacy and Safety of Anticoagulant Treatment in Acute Cardioembolic Stroke

A Meta-Analysis of Randomized Controlled Trials

Maurizio Paciaroni, MD; Giancarlo Agnelli, MD; Sara Micheli, MD Valeria Caso, MD, PhD

From the Stroke Unit, Department of Internal Medicine, University of Perugia, Perugia, Italy.

Correspondence to Maurizio Paciaroni, MD, Stroke Unit, Department of Internal Medicine, University of Perugia, Ospedale Santa Maria della Misericordia, Sant’Andrea delle Fratte, Perugia, Italy. E-mail: mpaciaroni{at}libero.it

	Abstract

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Background and Purpose— The role of anticoagulant treatment for acute cardioembolic stroke is uncertain. We performed an updated meta-analysis of all randomized trials to obtain the best estimates of the efficacy and safety of anticoagulants for the initial treatment of acute cardioembolic stroke.

Methods— Using electronic and manual searches of the literature, we identified randomized trials comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids), started within 48 hours, with other treatments (aspirin or placebo) in patients with acute ischemic cardioembolic stroke. Two reviewers independently selected studies and extracted data on study design, quality, and clinical outcomes, including death or disability, all strokes, recurrent ischemic stroke, and cerebral symptomatic bleeding. Odds ratios for individual outcomes were calculated for each trial and data from all the trials were pooled using the Mantel-Haenszel method.

Results— Seven trials, involving 4624 patients with acute cardioembolic stroke, met the criteria for inclusion. Compared with other treatments, anticoagulants were associated with a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0% versus 4.9%, odds ratio 0.68, 95% CI: 0.44 to 1.06, P=0.09, number needed to treat=53), a significant increase in symptomatic intracranial bleeding (2.5% versus 0.7%, odds ratio 2.89; 95% CI: 1.19 to 7.01, P=0.02, number needed to harm=55), and a similar rate of death or disability at final follow up (73.5% versus 73.8%, odds ratio 1.01; 95% CI: 0.82 to 1.24, P=0.9).

Conclusions— Our findings indicate that in patients with acute cardioembolic stroke, early anticoagulation is associated with a nonsignificant reduction in recurrence of ischemic stroke, no substantial reduction in death and disability, and an increased intracranial bleeding.

Key Words: anticoagulants • cardioembolism • cerebral bleeding • stroke

	Introduction

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Emboli arising from the heart account for at least 20% of ischemic strokes. Nonvalvular atrial fibrillation (NVAF) is the most common cause of cardiac embolism, is associated with a 5-fold increased risk of stroke, and accounts for nearly 25% of strokes in patients older than 80 years.^1,2

The risk of early recurrent ischemic stroke, defined as a new stroke of presumed embolic origin occurring within the first 2 weeks, is higher in patients with NVAF than in patients with stroke resulting from other causes, and the rate varies between 0.1% and 1.3% per day.^3,4 The role of immediate anticoagulation to reduce early recurrence and improve functional outcome in acute cardioembolic ischemic stroke is controversial. However, unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), or heparinoids are commonly used in routine clinical practice outside clinical trials.

To further clarify the role of anticoagulants (UFH, LMWH, heparinoid) for the treatment of acute cardioembolic stroke, we performed an updated meta-analysis of all randomized trials comparing anticoagulants, started within 48 hours, with other treatments (placebo or aspirin) for the initial treatment of acute cardioembolic stroke. Our outcomes were death or disability, all strokes, recurrent ischemic stroke, and cerebral symptomatic bleeding.

	Methods

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A protocol was prospectively developed, which detailed the specific objectives, criteria for study selection, the approach to assessing study quality, clinical outcomes, and statistical methodology.

Study Identification
We aimed to identify all relevant published and unpublished randomized trials comparing anticoagulants (UFH, LMWH, heparinoids) with other treatments (placebo or aspirin) for the initial treatment (within 48 hours) of acute cardioembolic ischemic stroke. The following anticoagulant regimens were to be included: subcutaneous and intravenous UFH, subcutaneous LMWHs, and subcutaneous and intravenous heparinoids. We searched electronic databases (MEDLINE and EMBASE) from January 1980 to February 2006 and the Cochrane Library (2006, Issue 1) using the terms stroke, cardioembolism, heparin, heparinoids, low-molecular-weight heparin, anticoagulants, randomized controlled trial, and controlled clinical trial. Bibliographies of journal articles were manually searched to locate additional studies and abstracts from major international meetings were reviewed to locate any unpublished studies. Relevance of studies was assessed using a hierarchical approach based on title, abstract, and the full manuscript. We included in this review randomized controlled trials that compared anticoagulants with other treatments or placebo in patients with acute stroke resulting from etiologies other than cardioembolism but only when it was possible to extrapolate data regarding patients with cardioembolism. If any of these data were not available in the publications, further information was sought by correspondence with the authors.

Study Selection
Criteria for inclusion were: (1) randomization within 48 hours from stroke onset; (2) inclusion of patients with objectively diagnosed stroke of presumed cardioembolic origin; (3) comparison of anticoagulants (UFH, LMWH, heparinoid) with other treatments (placebo or aspirin) for the initial therapy of cardioembolic ischemic stroke; and (4) use of objective methods to assess one or more of the study outcomes.

Assessment of Study Quality
We adopted the criteria for study quality outlined by Schultz and colleagues⁵ in the evaluation of studies included in our meta-analysis. These criteria include: (1) proper generation of the treatment allocation sequence; (2) proper concealment of the allocation sequence; (3) blinding of the patient and the investigator assessing clinical outcomes to treatment allocation; and (4) completeness of follow up.

Data Extraction
Two investigators (M.P., S.M.) independently extracted data on study design, study quality, and the following efficacy and safety outcomes at 14 days: (1) all strokes (ischemic or hemorrhagic); (2) recurrent ischemic stroke; (3) symptomatic intracranial hemorrhage; (4) pulmonary embolism and, at final follow up, (5) death or disability. The data abstracted for each trial were confirmed by a third investigator (V.C.) and any disagreements resolved by consensus.

Outcomes
The efficacy outcomes were the composite of death or disability at final follow up (at least 3 months), all strokes (ischemic and hemorrhagic) within 14 days, early recurrent stroke (within 14 days), and pulmonary embolism; the safety outcome was symptomatic intracranial bleeding.

Study outcomes were analyzed comparing the results from trials with anticoagulants versus aspirin or the results from trials with anticoagulants versus placebo.

Statistical Analysis
Given the presence of possible statistical heterogeneity resulting from clinical diversity of the selected studies, we used a random-effects model based on the Mantel-Haenszel method⁶ for combining results from the individual trials. We calculated the odds ratio (OR) and 95% CIs. Tests of heterogeneity were calculated using the Mantel-Haenszel method. A P value <0.05 was considered statistically significant except for heterogeneity testing, in which statistical significance was accepted at a P value of 0.10. All statistical calculations were performed using Review Manager.⁷

	Results

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Study Selection
The process of study selection is showed in Figure 1. Our search identified 766 potentially eligible citations. After scanning titles and abstracts, 743 citations were excluded and 23 were retained for further evaluation. Eighteen studies were excluded for the following reasons: data on cardioembolic strokes were not reported in 9 trials^8–16; one trial did not have a control group¹⁷; 2 trials were nonrandomized^18,19; randomization was performed after 48 hours from onset in 2 trials^20,21; cardioembolic strokes were excluded in 3 trials^22–24; and no computed tomography scan before randomization was performed in one trial.²⁵ Two studies were reincluded in the analysis because the authors provided us with data on cardioembolic strokes not previously reported in the original published articles.^14,16

View larger version (31K): [in this window] [in a new window]   Figure 1. Process of study selection.

Study Design
The design of 7 studies included^{14,16,26–30} in this meta-analysis are summarized in Table 1. All studies included patients with cardioembolic ischemic stroke (n=4624) randomized within 48 hours from stroke onset. Atrial fibrillation was present in 3797 patients and other mixed cardioembolic sources in 827. Three trials used UFH,^16,26,30 3 trials LMWH (TAIST tinzaparin, HAEST dalteparin, and FISS-bis nadroparin),^14,28,29 and one trial (TOAST) heparinoid (danaparoid).²⁷ In the CESG trial, the follow up was reported only at 14 days.³⁰

View this table: [in this window] [in a new window]   TABLE 1. Randomized Trials With Anticoagulants in Patients With Cardioembolic Stroke

Study Quality
Reporting of study quality data was incomplete. Randomized treatment allocation sequences were block-randomized by assignment to sequential numbered packages containing either active drug and corresponding placebo (double-dummy masking) in the HAEST trial²⁸ and in the TAIST trial¹⁴; sequentially numbered boxes blinded to doctor, patient, and assessor in the FISS-bis trial²⁹; permuted blocks with randomly ordered sizes of 6, 6, and 4 (randomization lists pharmacy controlled) blinded to doctor, patient, and assessor in TOAST²⁷; telephone randomization in IST²⁶, using a computer program from Camerlingo¹⁶ and with sealed envelopes (opaque and sequentially) in CESG.³⁰ Both patients and investigators were blind to treatment allocation in 5 of the 7 trials. The number of patients lost to follow up was reported in 6 trials included in our meta-analysis (none in CESG, HAEST, and Camerlingo; 11 in TAIST; 25 patients overall in TOAST without specific information about the number of patients with cardioembolic stroke; 99.99% completed for 14 days outcome and 99.2% completed 6-month outcome in IST).

Outcomes
Data on the outcomes are presented in Table 2 and Figures 2 and 3A through C and summary data for individual components of these outcomes are presented in Table 3. Compared with other treatments, anticoagulants were associated with a nonsignificant difference in death or disability at final follow up (73.5% versus 73.8%, OR 1.01; 95% CI: 0.82 to 1.24, P=0.9, P for heterogeneity=0.21). The difference in death or disability was statistically significant in only one trial¹⁶ (58.5% versus 74.1%, OR 0.49, 95% CI: 0.26 to 0.93). The difference in all strokes (ischemic and hemorrhagic) was not significant (OR 1.18; 95% CI: 0.74 to 1.88, P=0.49, P for heterogeneity=0.25). Anticoagulants were associated with a nonsignificant reduction in recurrent stroke within 7 to 14 days (3.0% versus 4.9%, OR 0.68; 95% CI: 0.44 to 1.06, P=0.09, number needed to treat=53) but were associated with a significant increase in symptomatic intracranial bleeding (2.5% versus 0.7%, OR 2.89; 95% CI: 1.19 to 7.01, P=0.02, number needed to harm=55).

View this table: [in this window] [in a new window]   TABLE 2. Pooled Estimated of Effects of Anticoagulants versus Placebo or Aspirin on Hemorrhagic Stroke, Recurrent Ischemic Stroke, and Pulmonary Embolism

View larger version (34K): [in this window] [in a new window]   Figure 2. Death or disability in trials comparing anticoagulants with other treatments (a, anticoagulants versus placebo or aspirin; b, anticoagulants versus aspirin; c, anticoagulants versus placebo) for the initial treatment of acute cardioembolic stroke.

View larger version (31K): [in this window] [in a new window]   Figure 3. All strokes (ischemic and hemorrhagic) in trials comparing anticoagulants with other treatments (a, anticoagulants versus placebo or aspirin; b, anticoagulants versus aspirin; c, anticoagulants versus placebo) for the initial treatment of acute cardioembolic stroke.

View this table: [in this window] [in a new window]   TABLE 3. Functional Outcome: Results of Trials With Anticoagulants in Patients With Acute Cardioembolic Stroke

Subgroup Analyses
Compared with placebo, anticoagulants were associated with a nonsignificant difference in death or disability at final follow up (OR 0.90; 95% CI: 0.67 to 1.22). Compared with aspirin, anticoagulants were associated with a nonsignificant trend in favor of aspirin in death or disability at final follow up (OR 1.14; 95% CI: 0.95 to 1.38).

Compared with aspirin, anticoagulants were not associated with a reduction in pulmonary embolism (OR 0.94; 95% CI: 0.44 to 2.00; P=0.87, P for heterogeneity=0.94).

Sensitivity Analyses
Sensitivity analyses were conducted to explore the robustness of our results. To identify any study that may have exerted a disproportionate influence on the summary treatment effect, we deleted studies one at a time. Deleting individual studies did not significantly alter the outcomes. The lack of positive trials with a large number of patients (only one small study showed a reduction in death or disability after the scheduled follow-up) and the fact that all the trials demonstrated similar no significant results argue against possible publication bias.

	Discussion

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This analysis shows that death and disability is not reduced by early anticoagulant treatment in patients with acute ischemic stroke presumably as a result of cardioembolism. Anticoagulants were associated with a nonsignificant reduction in recurrent stroke within 2 weeks as well as with a significant increase in symptomatic intracranial bleeding. With respect to previous systematic reviews,^31–33 this was focused exclusively on patients with cardioembolic stroke, these patients being those who should benefit the most from early anticoagulation and include new unpublished data.

The use of early anticoagulation in ischemic stroke has been a matter of debate for a long time. In the most recent of these debates, Caplan supported the use of UFH in selected patients as those with cardioembolic stroke with a high risk of early recurrence. Sandercock, on the other hand, took the stand that current data from randomized trials are not sufficient to support the use of UFH in acute ischemic stroke.^34,35

In the IST and CAST studies, patients with atrial fibrillation randomized to aspirin versus control and treated a mean of 20 hours after stroke onset showed trends toward a reduction in early recurrent stroke and an improvement of 6-month functional outcome.^36,37 In our analysis, mortality and disability in patients with cardioembolic stroke treated with aspirin were certainly not worse than in patients treated with anticoagulants. These data combined with the safety and ease of aspirin make early aspirin therapy reasonable for patients with acute stroke and atrial fibrillation.³⁸

In the single study in which anticoagulation was started within 3 hours from stroke onset, death or disability was reduced by anticoagulant treatment. These results should be interpreted with caution because other trials did subgroup analyses in hyperacute patients and showed neutral results. Several studies have suggested that besides its antithrombotic effects, UFH also modulates inflammation.^39–43 Thus, the positive effect of early heparin could be the result of either its antithrombotic effects and/or its modulation on the antiinflammatory pathway that appears relevant in the first hours. Whatever the mechanism for improvement, the benefit observed in patients treated within 3 hours suggests the need for further trials on the efficacy of very early administration of anticoagulants in acute cardioembolic stroke. In selecting the study population for these trials, size of ischemia, age, and blood pressure in the acute phase, all known as risk factors for hemorrhagic complications, should be considered.

In clinical trials on thrombolytic therapy for acute ischemic stroke, approximately 20% to 30% of patients had NVAF and thus, a stroke of presumed cardioembolic origin.^38,44–46 The option of treating with thrombolysis patients with acute ischemic stroke and NVAF is limited by the large volume of their brain infarcts, their old age, and the likelihood of symptomatic brain hemorrhage. However, some studies, after adjustment for extent and severity of ischemia, have demonstrated that NVAF is not associated with secondary hemorrhagic transformation after thrombolysis.⁴⁷ Furthermore, thrombolysis given within 3 hours of stroke onset appears to offer a benefit for patients with NVAF with acute ischemic stroke. Therefore, further clinical trials in the 3-hour time window need to compare anticoagulant treatment with thrombolysis or to consider anticoagulants for patients in whom thrombolytic therapy is contraindicated.

Deep vein thrombosis and pulmonary embolism are major causes of morbidity and mortality after ischemic stroke.^48,49 Heparin has a role in the prevention of deep vein thrombosis and pulmonary embolism.⁵⁰ In the IST, UHF-allocated patients had fewer pulmonary emboli recorded within 14 days (0.5% versus 0.8%; P=0.02), but, at 6 months, the rate of deaths or dependent patients was identical. In this analysis, the rates of pulmonary embolism were similar in patients treated with anticoagulants and in patients treated with aspirin.

The optimal timing to initiate oral anticoagulant therapy for secondary prevention was not addressed in this review. It seems reasonable to begin it as soon as the patient is medically and neurologically stable after repeating a computed tomography scan to exclude a hemorrhagic transformation or a large infarct. Empirically if the infarct is large or a hemorrhagic transformation is present, initiation of warfarin should be delayed for 2 to 3 weeks.

	Conclusions

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Our analysis does not support the early administration of anticoagulants in patients with acute ischemic stroke of cardioembolic origin to prevent early recurrence or to improve functional outcome. Early aspirin followed by vitamin K antagonists for long-term secondary prevention is reasonable. The result of a recent study showing an advantage of the very early administration of heparin (<3 hours from stroke onset) deserves further attention.

	Acknowledgments

 
We thank Phil Bath for the TAIST Investigators, Massimo Camerlingo, and Peter Sandercock, and Stephanie Lewis for the IST Collaborative Group for their availability to provide unpublished data to be included in this analysis.

Disclosures

Giancarlo Agnelli received honoraria as a member of the speaker bureau of Astra Zeneca and Bayer.

	Footnotes

 
Continuing medical education (CME) credit is available for this article. Go to http://cme.ahajournals.org to take the quiz.

Received April 24, 2006; revision received August 28, 2006; accepted September 25, 2006.

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				L. C. Guedes and J. M. Ferro A Systematic Review of Immediate Anticoagulation for Ischemic Stroke of Presumed Cardioembolic Origin Stroke, May 1, 2008; 39(5): e81 - e82. [Full Text] [PDF]

				M. Paciaroni, G. Agnelli, S. Micheli, and V. Caso Response to Letter by Guedes and Ferro Stroke, May 1, 2008; 39(5): e83 - e83. [Full Text] [PDF]

				G J Hankey When the patient fails to respond to treatment: TIAs that go on, and on Practical Neurology, April 1, 2008; 8(2): 103 - 111. [Abstract] [Full Text] [PDF]

				E. Doufekias, A. Z. Segal, and J. R. Kizer Cardiogenic and aortogenic brain embolism. J. Am. Coll. Cardiol., March 18, 2008; 51(11): 1049 - 1059. [Abstract] [Full Text] [PDF]

				S. T. Engelter, T. Brandt, S. Debette, V. Caso, C. Lichy, A. Pezzini, S. Abboud, A. Bersano, R. Dittrich, C. Grond-Ginsbach, et al. Antiplatelets Versus Anticoagulation in Cervical Artery Dissection Stroke, September 1, 2007; 38(9): 2605 - 2611. [Abstract] [Full Text] [PDF]

				H. B. van der Worp and J. van Gijn Acute Ischemic Stroke N. Engl. J. Med., August 9, 2007; 357(6): 572 - 579. [Full Text] [PDF]

				Additional articles abstracted in ACP Journal Club Evid. Based Med., August 1, 2007; 12(4): 126 - 126. [Full Text] [PDF]

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