Emergent Use of Anticoagulation for Treatment of Patients With Ischemic Stroke
Background— Several clinical trials have tested the potential utility of emergent anticoagulation for acute ischemic stroke.
Summary of Review— Rather than performing a meta-analysis that combines the data from several trials, this review focuses on individual studies. Although these trials do have inherent limitations, they demonstrate that emergent use of an anticoagulant is associated with a modest but significantly increased risk of hemorrhagic transformation of the ischemic stroke or serious nonneurological bleeding. The trials do not demonstrate a benefit from emergent anticoagulation in improving outcome, reducing mortality, and preventing early recurrent stroke.
Conclusions— These results suggest that most patients with acute stroke should not be treated with unfractionated heparin or other rapidly acting anticoagulants after stroke. Prevention of deep vein thrombosis and pulmonary embolism among bedridden patients is the only established indication for early anticoagulation after acute ischemic stroke.
For many years, anticoagulants have been a mainstay in the emergent treatment of patients with acute ischemic stroke. Many physicians prescribe anticoagulants in an effort to prevent neurological worsening, presumably by halting the propagation of thrombosis, helping maintain collateral flow and circulation, and forestalling early recurrent stroke, especially among patients with cardioembolism and large-artery atherosclerosis (artery-to-artery embolism).1,2⇓ Despite the widespread prescription of the rapidly acting anticoagulants, their use is controversial. Experts have given a broad spectrum of opinions.2–8⇓⇓⇓⇓⇓⇓ Surveys of practitioners have also demonstrated a lack of agreement about the value of these medications.9,10⇓ The uncertainty is due in large part to the lack of definitive data. A panel of the Stroke Council of the American Heart Association reviewed evidence regarding the value of emergent anticoagulation and found no strong evidence for its effectiveness in treating acute ischemic stroke.11 Since then, several clinical trials have examined the utility of early anticoagulant treatment. Their results are the focus of the present review because they provide a framework on which to make current decisions about the emergent use of rapidly acting anticoagulants.
Issues Related to the Design of Trials
Rather than performing a meta-analysis that combines the data from several trials, this review focuses on the individual studies. This approach was used because one trial is much larger than all the others combined; thus, its results would unduly sway a meta-analysis. In addition, differences between the trials, such as the diversity in populations, intervals to treatment, types of medications, and routes of administration, make the results of a meta-analysis somewhat dubious.
The characteristics of the different trials (Table 1) need to be assessed.4,8,12–17⇓⇓⇓⇓⇓⇓⇓ All the trials included randomization, but the International Stroke Trial (IST) was not a blinded trial, whereas the other trials were. Three trials compared anticoagulants with aspirin.14,16,17⇓⇓ The others compared anticoagulants with placebo.8,12,15⇓⇓ One trial that was examined compared 4 different doses of certoparin, a low molecular weight (LMW) heparin.13 The Trial of Org 10172 in Acute Stroke Treatment (TOAST) tested intravenously administered danaparoid.15 The other trials examined the utility of subcutaneously administered LMW heparins or heparin.8,12–14,16,17⇓⇓⇓⇓⇓ Only TOAST included a bolus dose to initiate treatment, monitored the degree of the anticoagulants, and made dose adjustments in response to the laboratory tests.15
As indicated by the thrombolytic trials, the interval from the onset of stroke until the initiation of treatment appears crucial. In the recent trials, the interval from stroke to onset until treatment could be up to 48 hours (Table 1). Thus, the relatively long time windows may have reduced the chances for success, and the prolonged interval may be a weakness of all the trials. Because of the importance of not administering an anticoagulant with a hemorrhagic stroke, most physicians would not give heparin without a CT scan showing the absence of bleeding. The requirement for baseline CT was included in most of the recent trials, but approximately one third of the patients in the IST did not have the test before treatment.14 The lack of the baseline brain-imaging study is one of the weaknesses of IST.
None of the trials required vascular imaging before treatment. Thus, there is little uniformity in evaluation or differentiation of subtypes of stroke. Although the trials can be criticized for not having cardiac and vascular testing before enrollment, proponents could suggest that the trials replicate clinical practice and that extensive time-consuming baseline testing might delay the initiation of therapy. Similar strategies have been used in most other large clinical trials, including the National Institute of Neurological Disorders and Stroke (NINDS) trials that tested recombinant tissue plasminogen activator (rtPA).18 The Heparin Aspirin Ischemic Stroke Trial (HAEST) restricted enrollment to patients with presumed cardioembolic stroke and used the presence of atrial fibrillation as a surrogate for the determination of this subtype.16 Although this approach has merit, one can assume that a sizable proportion of the enrolled patients probably had stroke due to noncardioembolic causes.
Safety of Emergent Anticoagulation
Hemorrhagic transformation is a potential complication of ischemic stroke, and all agents that affect coagulation have the capability of causing serious bleeding.19 When compared with thrombolytic agents (6% to 10% risk of hemorrhage), anticoagulants have a lower risk of major bleeding complications, but the risk with these agents appears to be greater than the risk with platelet antiaggregatory agents (1% to 2% risk)14,20–22⇓⇓⇓ (Table 2). Differences in the rates of hemorrhagic complications are noted between the trials, but these findings probably cannot be attributed to different agents or routes of administration. Instead, dissimilarities in the study populations, ancillary care, or monitoring for adverse experiences in the several trials might be the explanation. This hypothesis is supported by discrepancies of reported bleeding rates in the control groups among the several trials. Still, on the basis of the results of the trials, one can conclude that emergent administration of anticoagulants is associated with a moderate, but real, risk of symptomatic hemorrhagic transformation of the infarction.
The risk of symptomatic hemorrhagic transformation of the ischemic lesion is highest among patients with severe neurological impairments.22,23⇓ One trial reported that the risk of serious neurological bleeding was significantly increased with the administration of an anticoagulant among patients with a National Institutes of Health Stroke Scale score >15.15 This experience is similar to that reported by the NINDS trial of thrombolytic therapy.18 No study has evaluated whether specific CT findings are predictive of hemorrhagic complications after the administration of an anticoagulant. Chamorro et al23 reported that the risk of intracranial bleeding associated with heparin treatment was increased with high levels of anticoagulation. The trials that compared differing doses of anticoagulants have shown that the risk of bleeding rises among patients given the larger doses (Table 2). The recent trials did not involve the direct comparison of individual anticoagulants, but their data do not imply that heparin is either more dangerous or safer than the LMW compounds. The trials also do not demonstrate that subcutaneous administration of these agents is safer than intravenous administration or vice versa. There are no data showing that the use of a bolus dose to start treatment is especially dangerous.
Serious nonneurological hemorrhagic complications also occur with emergent anticoagulation. In the trials, serious nonneurological bleeding complications were as frequent and as important in causing morbidity as were symptomatic intracranial hemorrhages.8,13,15,24⇓⇓⇓
Although the rates of serious bleeding complications vary between trials, all the trials demonstrate an increased risk of hemorrhage with the administration of anticoagulants. These data support the contention that emergent anticoagulation cannot be administered with impunity, especially among persons with moderate-to-severe strokes. Although the risks are not prohibitive, they are sufficiently high to warrant strong evidence of efficacy to justify their use.
Prevention of Deep Vein Thrombosis
Up to one third of bedridden patients who have a paralyzed lower limb might develop a deep vein thrombosis while in the hospital, and secondary pulmonary embolism is a major cause of morbidity and mortality after ischemic stroke.24,25⇓ Current guidelines include recommendations for subcutaneous administration of heparin as an adjunctive therapy to prevent venous thromboembolism after stroke.11,26⇓ These recommendations can include LMW heparin or danaparoid as an alternative to unfractionated heparin.24,27⇓ Anticoagulants do have a role in the management of some patients with recent ischemic stroke as a measure to prevent deep vein thrombosis and, presumably, pulmonary embolism.
Prevention of Early Recurrent Stroke
Prevention of early recurrent stroke is often considered to be a primary indication for emergent anticoagulation.9,10⇓ Preventing recurrent stroke is a part of the management of all patients hospitalized with recent stroke. The primary issues relate to the timing of starting therapy and selection of the best therapy for the individual patient.28 Because of a perceived high risk of early recurrent embolism, anticoagulants are often prescribed to patients with cardioembolic stroke. In the design of a recent Norwegian trial,16 the investigators assumed a 12% two-week risk of recurrent embolism among patients with atrial fibrillation and a recent stroke. Reduction in such high rates of early recurrences could provide a strong rationale for emergent treatment with anticoagulants. However, data from control or placebo-treated groups in recent trials demonstrate that the risk of early recurrent stroke is much lower than previously calculated14,15,22⇓⇓ (Table 3). These data imply that the overall risk of early recurrent embolism is relatively low; thus, it will be difficult for any trial to demonstrate efficacy of any intervention that is aimed primarily at lowering this risk.
Some trials did not specifically look at the impact of anticoagulants on reducing the risk of early recurrent stroke. Although the trials report differing rates of recurrent stroke, these variations likely reflect the populations of patients enrolled in the trials rather than major differences in medications. The recent trials do not show a significant reduction in the rate of recurrent embolism with the emergent use of an anticoagulant (Table 3). No significant reduction in early recurrent stroke was noted with intravenous anticoagulation among patients in TOAST, including those with events ascribed to cardioembolism.15 Berge et al16 actually reported a higher rate of recurrent stroke among patients treated with LMW heparin than among those prescribed aspirin. At present, emergent administration of anticoagulants is not established as efficacious in preventing early recurrent embolization.
Halting Neurological Worsening
Approximately 20% to 40% of patients can have neurological deterioration during the first days after stroke.29 Because any neurological deterioration leads to a poor outcome, forestalling such a complication could speed neurological recovery and improve outcome.29 Heparin is often prescribed to patients who are diagnosed as having a stroke in evolution. Presumably, the anticoagulant might prevent the propagation of an intraluminal thrombus and could help maintain collateral blood flow, particularly in the microcirculation. A recent nonrandomized study also demonstrated no benefit from heparin in halting neurological worsening after stroke.30 In the trial of danaparoid, ≈10% of the patients treated with either placebo or danaparoid had deterioration during the treatment period15 (Table 4). The trial of dalteparin also did not find a reduction in the rate of worsening with treatment.16 These studies do not demonstrate the efficacy of anticoagulation in halting neurological worsening after stroke.
Reducing Mortality and Disability From Stroke
Despite an increase in the rate of symptomatic hemorrhagic transformation of the infarction and serious systemic bleeding, the use of anticoagulants has not been associated with an increased rate of early mortality. The recent trials do not show a significant decline in death or disability or increase in favorable outcomes with the administration of anticoagulants8,12–17⇓⇓⇓⇓⇓⇓ (Table 5). Although the rates of favorable and unfavorable outcomes differ between trials, these variations are not great and probably reflect differences in the populations of patients and designs of the trials. For example, the trials used different outcome measures and definitions for favorable responses to treatment. Still, all the trials have similar responses: no net benefit from urgent anticoagulation. One trial included prespecified analyses that examined treatment responses as influenced by the presumed cause of stroke and found a sustained benefit from treatment among patients with stroke ascribed to large-artery atherosclerosis.15 However, the size of the treatment groups was relatively small, and the results should not be considered definitive. Another trial could not demonstrate any benefit from treatment among patients with stroke attributed to large-artery atherosclerosis.17
Anticoagulation as an Adjunctive Therapy
In the future, the primary role for anticoagulants might be as an adjunctive treatment for patients who have received other interventions. There is a precedent for the use of combinations of medications; cardiologists often administer anticoagulants and antiplatelet-aggregating agents as adjuncts to thrombolytic therapy or emergent angioplasty and stenting in the treatment of patients with acute myocardial ischemia. Presumably, the adjunctive anticoagulant might help prevent reformation of a thrombus at the site of the arterial injury, such as at a fractured atherosclerotic plaque or an area of denuded endothelium. However, the present guidelines contraindicate the use of either anticoagulants or platelet antiaggregants within the first 24 hours after intravenous administration of rtPA among patients with ischemic stroke.31,32⇓ In 2 small studies, Grond et al33 and Trouillas et al34 administered heparin immediately after treatment with rtPA. The rates of intracranial hemorrhage were not higher than those expected with treatment with rtPA alone, and the rates of favorable outcomes were satisfactory. Two trials of prourokinase included heparin as part of the acute treatment regimen.35,36⇓ In the first study, the success of an improved rate of recanalization and the complication of hemorrhagic transformation were both increased among the patients who received the higher of 2 doses of heparin.35 Although the data are far from definitive, the success of these small studies is encouraging, and they should lead to additional research that tests the combination of mechanical or pharmacological thrombolysis and an anticoagulant.
Current Status of Emergent Anticoagulation
The recent clinical trials of anticoagulant therapy for treatment of patients with acute ischemic stroke can be criticized for methodological reasons. Still, these trials have tested these medications in a variety of paradigms and in a diversity of populations with acute stroke. The trials provide the most solid information about the potential utility of anticoagulants. All the studies, which have been performed by different groups of investigators around the world, have had similar results. They do not provide any data to support the emergent administration of anticoagulants as a monotherapy for treating most patients with acute ischemic stroke. One must conclude that there is no strong evidence to support the use of emergent anticoagulant therapy in the prevention of early recurrent stroke, in the arrest of neurological worsening, in the reduction of mortality, or in improving outcomes. Conversely, the studies show that anticoagulants are associated with an increase in the risk of serious bleeding complications, including symptomatic hemorrhagic transformation of the infarction.
Additional trials are presently under way. For example, Chamorro4 is leading a new trial of intravenously administered heparin that is given within 12 hours of the onset of stroke. Reducing the interval from the onset of stroke until the initiation of anticoagulant treatment might improve the chances of efficacy. In addition, part of the rationale for testing heparin is that it might have properties that could limit brain injury from acute inflammation. Because emergent anticoagulation is accompanied by an increased likelihood of serious bleeding events, the trials must provide robust evidence of efficacy to justify the risks. Unless these trials provide persuasive evidence regarding the usefulness of these agents, the future role of anticoagulants will likely be very limited.
The author thanks Cheryl Moores for her assistance in the preparation of the manuscript. The author also thank Drs José Biller, Patricia Davis, and Patrick Lyden for their review of the manuscript and their constructive comments.
Presented in part at the 4th World Stroke Congress, Melbourne, Australia, November 29, 2000, and the 6th International Symposium on Acute Stroke and Thrombolytic Therapy, Hamilton Island, Australia, December 2, 2000.
- Received September 14, 2001.
- Revision received November 22, 2001.
- Accepted November 26, 2001.
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- ↵Sandercock P. Intravenous unfractionated heparin in patients with acute ischemic stroke: a treatment to be used in the context of randomized trials only. Stroke. 2001; 32: 579.
- ↵Chamorro A. Immediate anticoagulation in acute focal brain ischemia revisited: gathering the evidence. Stroke. 2001; 32: 577–578.
- ↵Swanson RA. Intravenous heparin for acute stroke: what can we learn from the megatrials? Neurology. 1999; 52: 1746–1750.
- ↵Chamorro A. Heparin in acute ischemic stroke: the case for a new clinical trial. Cerebrovasc Dis. 1999; 9 (suppl 3): 16–23.
- ↵Marsh EE, Adams HP Jr, Biller J, Wasek P, Banwart K, Mitchell V, Woolson R. Use of antithrombotic drugs in the treatment of acute ischemic stroke: a survey of neurologists in practice in the United States. Neurology. 1989; 39: 1631–1634.
- ↵Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA. Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Circulation. 1994; 90: 1588–1601.
- ↵Diener HC, Ringelstein EB, von Kummer R, Langohr HD, Bewermeyer H, Landgraf H, Hennerici M, Welzel D, Grave M, Brom J, Weidinger G. Treatment of acute ischemic stroke with the low-molecular-weight heparin certoparin. Stroke. 2001; 32: 22–29.
- ↵The NINDS t-PA Stroke Study Group. Intracerebral hemorrhage after intravenous t-PA therapy for ischemic stroke. Stroke. 1997; 28: 2109–2118.
- ↵Fiorelli M, Bastianello S, von Kummer R, del Zoppo GJ, Larrue V, Lesaffre E, Ringleb AP, Lorenzano S, Manelfe C, Bozzao L. Hemorrhagic transformation within 36 hours of a cerebral infarct: relationships with early clinical deterioration and 3-month outcome in the European Cooperative Acute Stroke Study I (ECASS I) cohort. Stroke. 1999; 30: 2280–2284.
- ↵Jaillard A, Cornu C, Durieux A, Moulin T, Boutitie F, Lees KR, Hommel M. Hemorrhagic transformation in acute ischemic stroke. Stroke. 1999; 30: 1326–1332.
- ↵Chamorro A, Vila N, Saiz A, Alday M, Tolosa E. Early anticoagulation after large cerebral embolic infarction: a safety study. Neurology. 1995; 45: 861–865.
- ↵Bath PM, Iddenden R, Bath FJ. Low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials. Stroke. 2000; 31: 1770–1778.
- ↵Lensing AW. Anticoagulation in acute ischaemic stroke: deep vein thrombosis prevention and long-term outcomes. Blood Coagul Fibrinolysis. 1999; 10 (suppl 2): S123–S127.
- ↵Albers GW, Hart RG, Lutsep HL, Newell DW, Sacco RL. AHA Scientific Statement: supplement to the guidelines for the management of transient ischemic attacks: a statement from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks, Stroke Council, American Heart Association. Stroke. 1999; 30: 2502–2511.
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- ↵Adams HP Jr, Brott TG, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Kwiatkowski T, Lyden PD, Marler JR, Torner J, Feinberg W, Mayberg M, Thies W. Guidelines for thrombolytic therapy for acute stroke: a supplement to the guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a Special Writing Group of the Stroke Council, American Heart Association. Circulation. 1996; 94: 1167–1174.
- ↵Trouillas P, Nighoghossian N, Derex L, et al. Thrombolysis with intravenous rtPA in a series of 100 cases of acute carotid territory stroke: determination of etiological, topographic, and radiological outcome factors. Stroke. 1998; 29: 2529–2540.
- ↵del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke: PROACT Investigators Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998; 29: 4–11.
- ↵Furlan AJ, Higashida R, Wechsler L, Schultz G, PROACT II Investigators. PROACT II: recombinant prourokinase (r-ProUK) in acute cerebral thromboembolism: initial trial results. Stroke. 1999; 30: 234.