- Department of Neurosurgery, Stroke and Cerebrovascular Center of New Jersey at Capital Health, Two Capital Way, Suite 456, Pennington, NJ 08534, USA
Douglas L. Stofko
Department of Neurosurgery, Stroke and Cerebrovascular Center of New Jersey at Capital Health, Two Capital Way, Suite 456, Pennington, NJ 08534, USA
DOI:10.4103/2152-7806.132032Copyright: © 2014 Stofko DL This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
How to cite this article: Hakma Z, Stofko DL, Binning MJ, Liebman K, Veznedaroglu E. Retrospective study of Heparin Administration for Ischemic Stroke when there is an IV-tPA Contraindication. Surg Neurol Int 06-May-2014;5:62
How to cite this URL: Hakma Z, Stofko DL, Binning MJ, Liebman K, Veznedaroglu E. Retrospective study of Heparin Administration for Ischemic Stroke when there is an IV-tPA Contraindication. Surg Neurol Int 06-May-2014;5:62. Available from: http://sni.wpengine.com/surgicalint_articles/retrospective-study-of-heparin-administration-for-ischemic-stroke-when-there-is-an-iv-tpa-contraindication/
Background:The majority of patients presenting with an ischemic stroke arrive after the 3-4.5 h time window allowed for intravenous tissue plasminogen activator (IV tPA) administration. Most of the literature on heparin use in acute ischemic stroke does not describe dose-adjusted intravenous unfractionated heparin (IV UFH) without bolus, a common method of administration. This study was designed to test whether an anticoagulation regimen of intravenous dose-adjusted UFH with no bolus, in patients with a contraindication to IV TPA, administered within 24 h of an acute ischemic stroke could be effective and safe.
Methods:We conducted a retrospective study of 273 patients over two consecutive years with acute ischemic stroke, who were outside the window for IV tPA. All patients had imaging studies on admission. The primary outcome measure of the study was to evaluate the safety of dose-adjusted IV UFH use in the setting of acute stroke. We looked at duration of heparin infusion, average partial thromboplastin time (PTT) value, and the incidence of new hemorrhagic events.
Results:A total of 273 patients met the inclusion criteria. These patients received heparin infusion within 24 h of symptom onset. The duration of intravenous heparin infusion ranged from 1 to 18 days with a mean of 4 days. Mean PTT value was 72.4. Hemorrhagic complications occurred in 26 patients (9.5%), and included 12 asymptomatic petechial or hemorrhagic conversion (4.3%), 2 symptomatic intracranial hemorrhages (0.7%), 5 gastrointestinal bleeds (2 requiring transfusion and interventions), 2 patients experienced benign hematuria, 4 patients with groin hematomas, and one neck hematoma.
Conclusion:This study suggests that intravenous dose-adjusted UFH with no bolus can be administered to patients with acute ischemic stroke with relative safety.
Keywords: Anticoagulation, hemorrhagic complications, heparin, intravenous tissue plasminogen activator, stroke
Acute ischemic stroke is a common problem that carries a significant risk of mortality and morbidity. There are approximately 600,000 new cases of acute ischemic stroke diagnosed each year in the United States, resulting in approximately 150,000 deaths and 300,000 survivors with substantial disabilities.[
Current American Stroke Association/American Heart Association recommendations on the management of acute ischemic stroke do not recommend the early use of heparin because of an increased risk of bleeding complications.[
According to our literature review, there is an apparent lack of published data regarding immediate treatments for patients presenting with an IV tPA contraindication. The purpose of this study is to discuss the option of administering weight-based IV heparin to patients presenting within 24 h postischemic stroke, while assessing the safety of this intervention.
We conducted a retrospective study of 273 consecutive patients, from May of 2009 to June 2011, admitted to Capital Health Regional Medical Center with diagnosis of acute ischemic stroke outside the window for IV tPA. Any patient who received IV Heparin within 24 h of symptom onset was included. The primary goal of this study was to evaluate the safety of dose-adjusted IV UFH in the setting of acute stroke. All patients had imaging studies on admission and at 24 h postheparin infusion. Patients who were converted to oral anticoagulation received a head computed tomography (CT) prior to starting therapy. Intracranial and extracranial hemorrhages (ECH) were recorded, with symptomatic intracranial hemorrhages being characterized based on the National Institute for Neurological Disorders and Stroke (NINDS) criteria and severe ECH based on the need for blood transfusion. Heparin was discontinued depending on the severity of the hemorrhage and actively reversed with protamine if needed. Heparin was infused at a rate to keep the activated partial thromboplastin time (aPTT) between 60 and 80 with no initial bolus.
We looked at patients’ age, gender, length of stay, duration of heparin infusion, average aPTT value, necessity of endovascular or cranial procedures, use of aspirin, clopidogrel or warfarin on admission and during hospitalization, incidence of new hemorrhage, admission and discharge Glasgow Coma Score (GCS) as well as National Institute of Health Stroke Scale (NIHSS).
Approval from Capital Health Regional Medical Centers Institutional review board (IRB) was obtained and informed consent was waived since it was a retrospective study of prospectively collected data.
Patients were included if they met the following criteria: Aged between 18 and 90 years with a clinical diagnosis of acute ischemic stroke, known time of onset, and the patient was outside IV tPA time window or with a contraindication to IV tPA. We excluded patients who received IV tPA for this ischemic stroke, any evidence of intracranial hemorrhage on CT or known bleeding diathesis.
A total of 273 patients met the inclusion criteria, 149 males and 124 females. Patient ages ranged from 20 to 91, with an average age of 65 years. All patients had imaging studies on admission as part of the stroke protocol to rule out intracerebral hemorrhage. These patients received heparin infusion within 24 h of the onset, with the duration of intravenous heparin infusion ranging from 1 to 18 days, and a mean of 4 days. Mean PTT value was 72.47. Length of stay ranged from 1 to 36 days (with one outlier staying 77 days) and median length of stay was 6 days. The mean GCS and NIHSS on admission were 13.3 and 8.13, respectively. Both GCS and NIHSS improved on discharge to 14 and 6.41, respectively.
Of the 273 patients, 96 (35%) were discharged on long-term anticoagulation (warfarin), 156 (57%) on aspirin and 162 (59%) on clopidogrel [
Stroke remains a frequent and costly problem worldwide, but with the substantial advances made in the understanding of stroke mechanisms, risk factors, treatment options and advanced imaging modalities, new therapies are rapidly emerging. Currently, drugs that interfere with hemostasis and clot formation, such as anticoagulants and antiplatelet agents, are becoming the primary management of patients with cerebrovascular disease.[
The use of heparin in the management of acute ischemic stroke has been the subject of many studies, although few trials examined the use of IV UFH. For the most part, these studies have shown no benefit from heparin, with small decrease in the risk of stroke progression or recurrence being offset by an increase in hemorrhagic complications.[
The theoretical benefit of heparin is that it reduces the development of erythrocyte-fibrin thrombi, which form in regions of vascular stasis by activating antithrombin III, thereby preventing clot propagation. Several other studies suggested that in addition to its antithrombotic effects, UFH also modulates inflammation, thus the effect of early anticoagulation may be attributed to modulation of the inflammatory pathway that appears to be most relevant in the first few hours of ischemia.[
Some published data exists on IV heparin administration but tends to look at other time frames or a longer heparin administration.[
Since the publication of the International Stroke Trial (IST), treatment of acute ischemic stroke using heparin has become controversial.[
The European Rapid Anticoagulation Prevents Ischemic Damage (RAPID) Trial aimed to randomize 1400 patients with acute ischemic stroke to intravenous weight-adjusted UFH or aspirin (ASA) within 12 h of symptom onset.[
In the Trial of Org 10172 in Acute Stroke Treatment (TOAST) trial (acute stroke treatment), there was no benefit for heparinoid-treated patients, although in subgroup analysis, there was a trend toward increased benefit in patients with large strokes.[
Camerlingo et al.[
Our study has several limitations, the most important being the lack of a control group, which is common in retrospective review. Furthermore, since departmental protocol only required CT imaging at two time points, before the initiation of heparin therapy and 24 h after the initiation of therapy, the number of asymptomatic hemorrhages may be underestimated.
The present study aimed to evaluate the safety of heparin infusion in the setting of acute ischemic stroke when administered intravenously, without bolus and with rigorous monitoring using aPTT. We reviewed the charts of 273 patients and found an overall complication rate of 9%. However, most of these complications were asymptomatic petechial or hemorrhagic conversions found on follow up imaging. Our incidence of petechial and hemorrhagic events without a parenchymal hematoma is well within the accepted range of spontaneous conversion described in the literature for prospective double-blinded placebo-controlled studies.[
Our data included only two serious intracranial hemorrhages (0.7%), one from a ruptured fusiform partially thrombosed basilar aneurysm that was causing an embolic stroke and the other a pontine hemorrhagic conversion. Both patients expired as a result of these complications. In comparison, the incidence of symptomatic spontaneous hemorrhage in the placebo arm of the IST, CAST, and TOAST ranged from 0.3% to 0.9%.
Acute anticoagulation with parenteral unfractionated intravenous heparin for acute ischemic stroke remains an area of ongoing controversy with strong proponents and critics.[
The use of early anticoagulation in ischemic stroke has been a matter of much debate. This study suggests that intravenous dose-adjusted UFH with no bolus can be administered to patients with acute ischemic stroke with relative safety. Further studies will be necessary in patients who present with acute CVA who do not qualify for IV tPA regarding the use of heparin infusion. While intravenous heparin continues to be widely used around the world in the management of acute ischemic stoke, guidelines regarding its use cannot be formalized until there is an adequately powered study demonstrating the safety and efficacy of monitored intravenous heparin.
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