Guidelines for the Early Management of Patients With Ischemic Stroke

Guidelines for the Early Management of Patients With Ischemic Stroke


Guidelines for the Early Management of Patients With Ischemic Stroke
2005 Guidelines Update A Scientific Statement From the Stroke Council of the American Heart Association/American Stroke Association
Harold Adams, MD, FAHA; Robert Adams, MS, MD, FAHA; Gregory Del Zoppo, MD, MS, FAHA Larry B. Goldstein, MD, FAHA

Key Words: AHA/ASA Scientific Statements • stroke • thrombolytic therapy • anticoagulation • evaluation

This article serves as an update of "Guidelines for the Early Management of Patients With Ischemic Stroke," published in Stroke in 2003 (http://stroke.ahajournals.org/cgi/content/full/34/4/1056). This update is intended to reflect advances in the field since the publication of the full guidelines. See Tables 1 and 2, reprinted in this article from the 2003 document, for explanations of grade (strength of recommendation).


Brain Imaging

CT remains the most widely used neuroimaging technique for the evaluation of patients with suspected acute ischemic stroke. Quantitative CT-based scoring systems (eg, the Alberta Stroke Program Early CT Score [ASPECTS]) are useful for identifying patients who are unlikely to recover fully despite thrombolytic therapy.1 Substantial agreement between the ASPECTS rating performed in real time and the score obtained later by an expert can be achieved when used by an experienced reader, but correlations are not perfect (weighted 0.69, 95% CI 0.59 to 0.79).2 This scoring system has not been assessed in general clinical practice and is limited to use in patients with infarctions suspected to be in the distribution of the middle cerebral artery. In addition, advances in CT technology, including the development of CT angiography and perfusion studies, may affect future recommendations about the use of CT in the evaluation of patients with suspected stroke.

MRI techniques also are used widely in the assessment of patients with suspected stroke or transient ischemic attack (TIA). For example, a retrospective analysis of patients having diffusion-weighted MRI studies within 3 days of TIA demonstrated relevant abnormalities in 21% of cases.3 Changes in 44% of cases are detected by T2-weighted or fluid attenuation inversion recovery MRI studies.

A scientific statement authored by a panel of the American Heart Association focused on perfusion imaging in the setting of acute ischemic stroke was published simultaneously with the original 2003 ischemic stroke guidelines.4 Information about the advantages and disadvantages of each imaging technique is included in the statement. The panel concluded that more comparison testing of the different techniques is needed to determine their relative abilities to differentiate tissues having normal perfusion and reversible or irreversible ischemic injury. Clinical trials must determine whether perfusion data help forecast outcomes after stroke and the ability to triage patients to specific interventions.

The 2003 ischemic stroke guidelines indicated that additional research was needed to determine the utility of MRI as a substitute for CT among patients with suspected acute stroke because detection of acute intracerebral hemorrhage via MRI had not been fully validated. A study addressing this need has been reported. In comparison with CT, MRI detected intracranial bleeding with 100% sensitivity and 100% accuracy, as identified by 3 experienced readers. Three medical students also interpreted the studies with a sensitivity of 95%. Additional studies have produced similar results.5,6 These results suggest that MRI may replace CT in the initial screening for hemorrhage among patients with suspected stroke. Additional experience for detection in the acute setting in real time and outside specialized academic centers in the United States is needed. Besides its utility in the diagnosis of acute brain ischemia, MRI also may help in identifying patients with previous microhemorrhages that could be associated with an increased risk of bleeding secondary to thrombolysis.7,8

MRI with susceptibility-weighted imaging may be useful in detecting areas of hemorrhage after intraarterial thrombolysis in situations in which CT findings could be equivocal because of residual contrast staining.9 The importance of this finding needs clarification. Prospective studies are needed to determine whether the findings of susceptibility-weighted MRI affect either prognosis or treatment.

Brain imaging is required to guide the selection of acute interventions to treat patients with stroke (grade A, no change from 2003). For most cases and at most institutions, CT remains the most important brain imaging test; however, new studies suggest that MRI also may be used to detect acute intracerebral hemorrhage and that it could be an alternative to CT. Additional studies are under way. There is general agreement that perfusion and diffusion-weighted MRI may be helpful in diagnosing and treating patients with acute stroke under some circumstances, but logistical issues, including the availability of the equipment and the presence of physicians with expertise in interpreting the tests, limit the use of MRI. At present, no data are available to show that MRI is superior to CT for selecting patients who could be treated with intravenous recombinant tissue plasminogen activator (rtPA). The use of MRI outside the setting of clinical research studies should not delay treatment of a patient who is otherwise eligible for treatment with intravenous rtPA (grade B, no change from 2003).

Treatment of Arterial Hypertension

The treatment of arterial hypertension immediately after stroke is problematic, as stated in the 2003 guidelines. Since then, a placebo-controlled phase II safety trial tested the utility of candesartan administered from day 1 to hypertensive patients with acute ischemic stroke.10 At 12 months, patients treated with candesartan had improved survival and few subsequent vascular events. No differences in blood pressure values were noted, however, and the effects on the outcome of the stroke are not described. This preliminary observation must be confirmed by a larger clinical trial.

Pharmacological (Intravenous or Intraarterial) Thrombolysis

Symptomatic hemorrhagic transformation of the infarction remains the primary concern with the administration of intravenous rtPA in the treatment of acute ischemic stroke.11 A recent pooled analysis of several trials of rtPA confirms that symptomatic hemorrhagic transformation is the primary complication of acute treatment with rtPA.12 A meta-analysis of the postmarketing open-label studies demonstrates that the risk of hemorrhage is 5.2%.13 A subsequent report by the same group demonstrated a marked decline in major bleeding complications when the guidelines were followed.14 Schmulling et al15 found that previous use of aspirin does not increase the risk of symptomatic intracranial bleeding after the administration of rtPA. The studies show that rtPA can be given with an acceptable margin of safety in a community setting when the guidelines for selection and treatment of patients are followed.13

Hill et al16 reported orolingual angioedema in 9 of 176 patients treated with intravenous rtPA. In most cases, the findings were mild, transient, and contralateral to the involved cerebral hemisphere. They noted that the likelihood was increased among patients who were taking angiotensin-converting enzyme inhibitors and among those who had evidence of ischemia in the frontal cortex and insula on CT. Other cases of more severe edema of the throat and mouth also have been described.17–19 Although the previous use of angiotensin-converting enzyme inhibitors is not a contraindication for the administration of rtPA, physicians should be aware of this potential complication. Presumably, medications used to treat angioedema would be indicated to treat a severely affected patient.

A recent report offered a pooled analysis of data from several clinical trials of rtPA.12 The data from each of these trials have been reported independently. Although the trials used different definitions of outcomes, the combined analysis applied definitions used in the National Institute of Neurological Disorders and Stroke trials (eg, no or minimal disability at 3 months as measured by modified Rankin Scale, the Barthel Index, and the National Institutes of Health [NIH] Stroke Scale) plus a global statistical test. The lower 95% confidence limit for the adjusted odds ratio for a favorable outcome crossed unity at 4.5 hours from symptom onset. This finding suggests that some patients may benefit from treatment beyond the current 3-hour window; however, additional information is necessary to move the maximal time window to 4.5 hours in the guidelines. Ongoing studies are evaluating the potential utility of rtPA given >3 hours after the onset of stroke.

Hsia et al20 found that the subtypes of ischemic stroke do not influence responses to treatment with rtPA. This finding implies that the determination of the subtype of stroke (eg, cardioembolism, large artery atherosclerosis, or small artery occlusion) is not a prerequisite for the administration of rtPA.

Intraarterial administration of thrombolytic agents has considerable appeal.21 A review of the available data shows that intraarterial thrombolysis is associated with a reduction in mortality and an improvement in favorable outcomes after a stroke, but it is also associated with an increased risk of hemorrhagic complications.22 Additional studies have been published since the development of the 2003 guidelines. In general, the results are similar to those published previously.23–26 Studies testing the utility of intraarterial thrombolysis are ongoing. Recommendations for the design and organization of such trials were published recently.27 At present, no evidence is available to show that intraarterial thrombolysis is superior to intravenous treatment. Therapy should not be withheld from patients who are eligible for treatment with intravenous thrombolysis so that medications can be administered intraarterially, except in the setting of a comparative research clinical trial.

The combination of administering intravenous therapy and then intraarterial therapy is being tested. This strategy could allow for early treatment of stroke with intravenous medication while the resources to deliver intraarterial therapy are organized.21,28,29 Additional reports that have become available since the 2003 guidelines reflect mixed results.30,31 Clinical trials testing the utility of the combination of intravenous and intraarterial therapy are in progress, and additional data are needed to support a recommendation for combination treatment.

Using transcranial Doppler ultrasonography, Alexandrov and Grotta32 found that approximately one third of patients develop reocclusion of the artery after intravenous thrombolysis. Patients with partial recanalization were the most likely to experience reocclusion and poorer neurological outcomes. These results are stimulating research on adjunctive antithrombotic therapies that help maintain arterial patency. Among the interventions are anticoagulants and rapidly acting parenterally administered antiplatelet agents.15,33–36 Although preliminary results are promising, experience is limited. Additional data are needed before changing the current recommendations to withhold adjunctive antithrombotic therapy for the first 24 hours after administration of rtPA.

Because of the current time requirements for the administration of rtPA, all aspects of the healthcare system must respond with a sense of urgency. Community-wide stroke programs are increasing the number of patients that can be treated.37–39 Delays within the hospital emergency department also need to be addressed.39 Telemedicine and emergency air transportation are among the ways to speed the treatment of patients with acute stroke.40,41

Novel thrombolytic agents such as desmotoplase, reteplase, and tenecteplase are being evaluated, but prospective data comparing these drugs with intravenous rtPA are few. Although experience is limited, thrombolytic agents have been given successfully to children with acute ischemic stroke.42

Recommendations
The recommendation for the intravenous administration of rtPA within 3 hours of onset of stroke in carefully selected patients should not be changed (grade A, no change from 2003). The evidence is strong that all delays in treating patients should be avoided (grade A, new recommendation). Although intraarterial thrombolysis alone or in combination with intravenous thrombolysis holds great promise, the use of these approaches is preferable in the setting of randomized clinical trials. A correction is needed in Table 7 of the 2003 Guidelines. Patients with an INR level of 1.7 or below can be treated with rtPA.


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TABLE 7. Characteristics of Patients With Ischemic Stroke Who Could Be Treated With rtPA



Anticoagulants

Current data do not provide evidence in support of the efficacy of early anticoagulation in improving outcomes after acute ischemic stroke.43 The recommendations of the 2003 guidelines are in agreement with other statements indicating that most stroke patients do not need emergency administration of anticoagulants.44–46 Despite the lack of supporting data, anticoagulants are still given frequently.47

A preliminary clinical study of argatroban has been completed and the agent was deemed to be safe.48 Burak et al49 administered enoxaparin to 8 children with stroke and concluded that the low-molecular-weight heparin was a safe and effective alternative to heparin for children. Anticoagulants also are being explored as an adjunct to thrombolytic therapy.15 Although the preponderance of past acute anticoagulation trials has failed to show a benefit, newer clinical trials testing heparin and other anticoagulants continue.

Recommendations
No data are available to support changing the recommendations about the use of anticoagulants in the urgent treatment of patients with acute ischemic stroke.

Antiplatelet Aggregating Agents

Since the publication of the 2003 guidelines, Roden-Jullig et al50 have reported the results of a placebo-controlled trial of aspirin (325 mg/day) for the treatment of patients with stroke. The trial enrolled 441 patients (220 took aspirin) within 48 hours of the onset of stroke. Patients were treated for 5 days; no significant reduction in the rate of neurological worsening was noted. No differences in outcomes were noted at 3 months. This study was underpowered to detect the mild beneficial effects of aspirin identified in earlier megatrials. A small study found that the combination of aspirin and a low-molecular-weight heparin did not improve outcomes after stroke.51

Other rapidly acting antiplatelet agents are being evaluated for their usefulness in treating patients with stroke. These agents are being administered as a monotherapy or in combination with thrombolysis.33–36 In a placebo-controlled study, abciximab was administered within 6 hours of the onset of stroke. The results have been presented in abstract form and are apparently promising but have not been published.

Recommendations
Although the new data do not change the recommendation that most patients should receive aspirin within 48 hours of stroke, the data also support the conclusion that the effects of aspirin are modest (grade A, no change from 2003). Aspirin should not be considered as an alternative to intravenous thrombolysis or acute therapies aimed at improving outcomes after stroke. Additional research on abciximab or other rapidly acting antiplatelet agents is needed before any recommendation about their use can be made.

Volume Expansion and Drug-Induced Hypertension

Medical measures to improve cerebral blood flow are being evaluated. In addition to its ability to improve flow to the ischemic region, albumin may have neuroprotective effects and is being tested. In a pilot study, Hillis et al52 found that drug-induced hypertension can improve blood flow and lessen the neurological consequences of stroke. This regimen has been used to treat patients with vasospasm after subarachnoid hemorrhage. Although drug-induced hypertension holds promise, this therapy may be associated with an increased risk of brain edema, hypertensive encephalopathy, or hemorrhagic transformation of the infarction. Additional vasopressor-related complications may include cardiac ischemia or arrhythmias. The intervention also may require admission to an intensive care unit and close monitoring. Further testing of drug-induced hypertension is in progress.

Recommendations
At present, drug-induced hypertension cannot be recommended for the treatment of most patients with ischemic stroke (grade A, new recommendation).

Surgical and Endovascular Procedures

Gay et al53 successfully performed carotid endarterectomy in 21 patients with acute ischemic symptoms. In another study of 67 patients, emergency carotid endarterectomy achieved recanalization in all but 5 cases.54 The patients who were selected for surgery had normal preoperative flow in the middle cerebral artery. The aim was to avoid performing surgery on the internal carotid artery if an ipsilateral embolic occlusion of the middle cerebral artery had already occurred. Another study found that the presence of a diffusion/perfusion mismatch could be used to help select patients for surgery.55

Endovascular and adjunctive mechanical thrombolytic methods include lasers, intraarterial suction devices, snares, angioplasty, and clot-retrieval devices.56,57 In some cases, these devices have been used in conjunction with pharmacological thrombolysis.58 In addition, therapeutic ultrasonography has been used to help break fibrin monomers, dissolve thrombi, and improve recanalization.59,60 Although these preliminary reports suggest that mechanical thrombolysis has great potential for the treatment of patients with acute ischemic stroke, these procedures have not been tested sufficiently to make any recommendation about their use.

Recommendations
At present, none of the methods of mechanical thrombolysis has been adequately tested to draw conclusions about efficacy. These interventions cannot be recommended outside the setting of clinical trials (grade A, no change from 2003).

Neuroprotective Agents

The last full guideline statement reviewed the results of several clinical trials that tested putative neuroprotective agents. No agent had demonstrated clinical benefit. Since the publication of the guidelines, the results of the IMAGES (Intravenous Magnesium Efficacy in Stroke) study have been reported.61 No overall difference in outcomes was noted between patients given magnesium and patients given placebo when the medication was administered within 12 hours of the onset of stroke; however, only 3% of the patients were enrolled within 3 hours of the onset of symptoms. Another trial of magnesium is under way62; in this trial, the medication is initiated while the patient is being transported to the hospital.

Citicoline is another putative neuroprotective agent that has been studied extensively. Although no significant benefit was associated with use of citicoline based on the primary, predetermined end points of any of the stroke trials, Davalos et al performed a meta-analysis of individual patient data.63 The analysis tested the hypothesis of whether 6 weeks of treatment with oral citicoline would improve outcomes at 3 months. Data from patients receiving various doses of citicoline or placebo who were enrolled in 4 clinical trials were analyzed. Only patients with compatible neuroimaging results, a moderate-to-severe neurological deficit (NIH Stroke Scale score 8), and a prestroke modified Rankin Scale score of 0 or 1 were included. Recovery was assessed on the basis of a global estimate of effect on the modified Rankin Scale, NIH Stroke Scale, and the Barthel Index. Recovery at 3 months was found in 25.2% of citicoline-treated patients versus 20.2% of placebo-treated patients (P=0.0034). The data for this exploratory, post hoc analysis were obtained from a highly selected group of patients. Of particular concern is that none of the individual clinical trials, which were the source of the data, was able to find a benefit from treatment with citicoline. Thus, additional research is needed to substantiate these results.

Recommendations
At present, no agent with putative neuroprotective effects can be recommended for the treatment of patients with acute ischemic stroke (grade A, no change from 2003).

Nutrition and Hydration

In a randomized trial, the FOOD (Feed Or Ordinary Diet) Trial Collaboration is testing the utility of several feeding strategies including oral supplementation, early versus delayed nasogastric tube feeding, and nasogastric versus percutaneous endoscopic gastrostomy feeding. A preliminary report based on 3012 patients indicates that poor baseline nutritional status is associated with worse outcomes at 6 months.64 Although weakened, this relationship persists after adjustment for other factors including the patient’s age, prestroke functional level, living conditions, and severity of stroke. A poor nutritional status was associated with an increased risk of infections including pneumonia, gastrointestinal bleeding, and pressure sores. Data about the effectiveness of specific therapies aimed at improving nutrition are not yet available. Still, these data provide a strong rationale for assessment of the patient’s nutritional status at the time of admission. In addition, measures should be implemented to maintain or improve the nutritional status of all patients with recent stroke.

Recommendations
Assessment of the patient’s baseline nutritional status and institution of measures to correct any major nutritional problems are recommended (grade C, new recommendation).

Hypothermia

Small preliminary clinical studies suggest that hypothermia may be feasible and beneficial for treatment of acute stroke.65–68 Two important articles in the New England Journal of Medicine showed significant benefits for hypothermia in cardiac arrest survivors.69,70 Hypothermia for acute stroke is a promising area for development, but data are insufficient to recommend it.

Table 6

Table 6 of the 2003 Guidelines has been updated with the table on page 920. The 2003 Guidelines online now show this update, and the table is being printed here for reference.


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TABLE 6. Approach to Elevated Blood Pressure in Acute Ischemic Stroke




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Disclosure




Footnotes

The American Heart Association makes every effort to avoid any actual or potential conflicts of interest that may arise as a result of an outside relationship or a personal, professional, or business interest of a member of the writing panel. Specifically, all members of the writing group are required to complete and submit a Disclosure Questionnaire showing all such relationships that might be perceived as real or potential conflicts of interest.

This statement was approved by the American Heart Association Science Advisory and Coordinating Committee on January 19, 2005. A single reprint is available by calling 800-242-8721 (US only) or writing the American Heart Association, Public Information, 7272 Greenville Ave, Dallas, TX 75231-4596. Ask for reprint No. 71-0317. To purchase additional reprints: up to 999 copies, call 800-611-6083 (US only) or fax 413-665-2671; 1000 or more copies, call 410-528-4121, fax 410-528-4264, or e-mail kgray@lww.com. To make photocopies for personal or educational use, call the Copyright Clearance Center, 978-750-8400.

Expert peer review of AHA Scientific Statements is conducted at the AHA National Center. For more on AHA statements and guidelines development, visit http://www.americanheart.org/presenter.jhtml?identifier=3023366.

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Previous version

Guidelines for the Early Management of Patients With Ischemic Stroke: A Scientific Statement From the Stroke Council of the American Stroke Association
Harold P. Adams, Jr, Robert J. Adams, Thomas Brott, Gregory J. del Zoppo, Anthony Furlan, Larry B. Goldstein, Robert L. Grubb, Randall Higashida, Chelsea Kidwell, Thomas G. Kwiatkowski, John R. Marler, and George J. Hademenos
Stroke 2003 34: 1056-1083. [Extract] [Full Text] [PDF]