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Antithrombotic and Thrombolytic Therapy, 8th Ed : ACCP Guidelines: ANTITHROMBOTIC AND THROMBOLYTIC THERAPY, 8TH ED: ACCP GUIDELINES |

Antithrombotic and Thrombolytic Therapy for Ischemic Stroke*: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition) FREE TO VIEW

Gregory W. Albers, MD, Chair; Pierre Amarenco, MD; J. Donald Easton, MD; Ralph L. Sacco, MD; Philip Teal, MD
Author and Funding Information

*From Stanford University Medical Center (Dr. Albers), Stanford Stroke Center, Palo Alto, CA; Department of Neurology and Stroke Center (Dr. Amarenco), Bichat University Hospital and Medical School, Paris, France; Department of Neurology (Dr. Easton), RI Hospital-Brown Medical School, Providence, RI; Department of Neurology (Dr. Sacco), Miller School of Medicine, University of Miami, Miami, FL; and The University of British Columbia (Dr. Teal), Vancouver, BC, Canada.

Correspondence to: Gregory W. Albers, MD, Stanford University Medical Center, Stanford Stroke Center, 701 Welch Rd, Building B Ste. 325, Palo Alto, CA 94304-1705; e-mail: albers@stanford.edu



Chest. 2008;133(6_suppl):630S-669S. doi:10.1378/chest.08-0720
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This article about treatment and prevention of stroke is part of the Antithrombotic and Thrombolytic Therapy: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Grade 1 recommendations are strong and indicate that the benefits do, or do not, outweigh risks, burden, and costs. Grade 2 suggests that individual patients’ values may lead to different choices (for a full understanding of the grading, see the “Grades of Recommendations” chapter by Guyatt et al, CHEST 2008; 133:123S–131S). Among the key recommendations in this chapter are the following: For patients with acute ischemic stroke, we recommend administration of IV tissue plasminogen activator (tPA) if treatment is initiated within 3 h of clearly defined symptom onset (Grade 1A). For patients with acute ischemic stroke of > 3 h but < 4.5 h, we suggest clinicians do not use IV tPA (Grade 2A). For patients with acute stroke onset of > 4.5 h, we recommend against the use of IV tPA (Grade 1A). For patients with acute ischemic stroke who are not receiving thrombolysis, we recommend early aspirin therapy (Grade 1A). For acute ischemic stroke patients with restricted mobility, we recommend prophylactic low-dose subcutaneous heparin or low-molecular-weight heparins (Grade 1A). For long-term stroke prevention in patients with noncardioembolic stroke or transient ischemic attack (TIA) [ie, atherothrombotic, lacunar, or cryptogenic], we recommend treatment with an antiplatelet agent (Grade 1A), including aspirin (recommended dose, 50–100 mg/d), the combination of aspirin and extended-release dipyridamole (25 mg/200 mg bid), or clopidogrel (75 mg qd). In these patients, we recommend use of the combination of aspirin and extended-release dipyridamole (25/200 mg bid) over aspirin (Grade 1A) and suggest clopidogrel over aspirin (Grade 2B), and recommend avoiding long-term use of the combination of aspirin and clopidogrel (Grade 1B). For patients who are allergic to aspirin, we recommend clopidogrel (Grade 1A). In patients with atrial fibrillation and a recent stroke or TIA, we recommend long-term oral anticoagulation (target international normalized ratio, 2.5; range, 2.0 to 3.0) [Grade 1A]. In patients with venous sinus thrombosis, we recommend unfractionated heparin (Grade 1B) or low-molecular-weight heparin (Grade 1B) over no anticoagulant therapy during the acute phase.

1.1 IV tPA for Acute Ischemic Stroke Within 3 h of Symptom Onset

1.1.1. For eligible patients (see inclusion and exclusion criteria listed below), we recommend administration of IV tPA in a dose of 0.9 mg/kg (maximum of 90 mg), with 10% of the total dose given as an initial bolus and the remainder infused over 60 min, provided that treatment is initiated within 3 h of clearly defined symptom onset (Grade 1A).

Underlying values and preferences: This recommendation places relatively more weight on overall prospects for long-term functional improvement despite the increased risk of symptomatic intracerebral hemorrhage in the immediate peristroke period.

1.1.2. We recommend that patients who are eligible for tPA be treated as quickly as possible within the 3-h time limit (Grade 1A).

Remark: All unnecessary delays must be avoided as the benefits of tPA therapy diminish rapidly over time. 1.1.3. For patients with extensive (more than one third of the middle cerebral artery territory) and clearly identifiable hypodensity on CT, we suggest not using of tPA (Grade 2B).

1.2 IV tPA for Acute Ischemic Stroke Between 3 to 6 h of Symptom Onset

1.2. For patients with acute ischemic stroke of > 3 h but < 4.5 h we suggest clinicians do not use IV tPA (Grade 2A). For patients with acute stroke onset of > 4.5 h, we recommend against the use of IV tPA (Grade 1A).

Underlying values and preferences: This recommendation assumes a relatively low value on small increases in long-term functional improvement, a relatively high value on avoiding acute intracranial hemorrhage and death, and a relatively high degree of risk aversion.

1.3 IV Streptokinase for Acute Ischemic Stroke Between 0 and 6 h of Symptom Onset

1.3. For patients with acute ischemic stroke, we recommend against streptokinase (Grade 1A).

1.4 Intraarterial Thrombolysis for Acute Ischemic Stroke

1.4.1. For patients with angiographically demonstrated middle cerebral artery occlusion and without major early infarct signs on the baseline CT or MRI scan, who can be treated within 6 h of symptom onset, we suggest intraarterial thrombolytic therapy with tPA for selected patients in centers with the appropriate neurologic and interventional expertise (Grade 2C).

1.4.2. For patients with acute basilar artery thrombosis and without major CT/MRI evidence of infarction, we suggest either intraarterial or IV thrombolysis with tPA depending on available resources and capabilities (Grade 2C).

2.1 Anticoagulants for Altering Outcomes Among Acute Stroke in Patients Not Eligible for Thrombolysis

2.1. For patients with acute ischemic stroke, we recommend against full-dose anticoagulation with IV, SC, or low-molecular-weight heparins or heparinoids (Grade 1B).

2.2 Antiplatelet Agents for Altering Outcomes in Acute Stroke Patients Not Eligible for Thrombolysis

2.2. For patients with acute ischemic stroke who are not receiving thrombolysis, we recommend early aspirin therapy (initial dose of 150–325 mg) [Grade 1A].

2.3 Antithrombotic Therapy for Prevention of Deep Vein Thrombosis and Pulmonary Embolism in Acute Ischemic Stroke

2.3.1. For acute stroke patients with restricted mobility, we recommend prophylactic low-dose SC heparin or low-molecular-weight heparins (Grade 1A).

2.3.2. For patients who have contraindications to anticoagulants, we recommend intermittent pneumatic compression (IPC) devices or elastic stockings (Grade 1B).

3.1 IPC for Deep Vein Thrombosis/Pulmonary Embolism Prophylaxis in Patients With Intracerebral Hematoma

3.1. In patients with an acute intracerebral hematoma (ICH), we recommend the initial use of IPC devices (Grade 1B).

3.2 Heparin for Deep Vein Thrombosis/Pulmonary Embolism Prophylaxis in Patients With ICH

3.2. In stable patients, we suggest low-dose SC heparin as soon as the second day after the onset of the hemorrhage (Grade 2C).

Underlying values and preferences: Given the uncertainty about the risk of heparin in this setting, this recommendation places a relatively high value on reducing the consequences of thromboembolism and a relatively lower value on minimizing the risk of cerebral rebleeding.

4.1 Prevention of Cerebral Ischemic Events in Patients With Noncardioembolic TIA or Stroke: Antiplatelet Drugs vs Placebo or vs an Alternative Antiplatelet Drug

4.1.1. In patients who have experienced a noncardioembolic stroke or TIA (ie, atherothrombotic, lacunar, or cryptogenic), we recommend treatment with an antiplatelet drug (Grade 1A). Aspirin, the combination of aspirin, 25 mg and extended-release dipyridamole, 200 mg bid, and clopidogrel (75 qd) are all acceptable options for initial therapy. We recommend an aspirin dose of 50–100 mg/d over higher aspirin doses (Grade 1B).

4.1.2. In patients who have experienced a noncardioembolic stroke or TIA, we recommend using the combination of aspirin and extended-release dipyridamole (25/200 mg bid) over aspirin (Grade 1A) and suggest clopidogrel over aspirin (Grade 2B).

Underlying values and preferences: The implementation of the recommendation to use the combination of aspirin and extended-release dipyridamole over aspirin may vary based on cost, tolerability, availability, ease of use, and absolute risk.

4.1.3. In most patients with a noncardioembolic stroke or TIA, we recommend avoiding long-term use of the combination of aspirin and clopidogrel (Grade 1B). In those with a recent acute myocardial infarction, other acute coronary syndrome, or a recently placed coronary stent, we recommend clopidogrel plus aspirin (75–100 mg) [Grade 1A]. The optimal duration of dual antiplatelet therapy depends on the specific cardiac indication (see other articles in this supplement).

4.1.4. For patients who are allergic to aspirin, we recommend clopidogrel (Grade 1A).

4.2 Prevention of Noncardioembolic Cerebral Ischemic Events: Oral Anticoagulants

4.2.1. For patients with noncardioembolic stroke or TIA, we recommend antiplatelet agents over oral anticoagulation (Grade 1A).

4.3 Prevention of Cerebral Ischemic Events in Patients Undergoing Carotid Endarterectomy: Antiplatelet Agents

4.3. In patients undergoing carotid endarterectomy, we recommend aspirin (50–100 mg/d) prior to and following the procedure (Grade 1A).

4.4 Prevention of Cardioembolic Cerebral Ischemic Events

4.4.1. In patients with atrial fibrillation who have suffered a recent stroke or TIA, we recommend long-term oral anticoagulation (target INR, 2.5; range, 2.0-3.0) [Grade 1A].

4.4.2. For patients with cardioembolic stroke who have contraindications to anticoagulant therapy, we recommend aspirin at a dose of 75–325 mg/d (Grade 1B).

4.4.3. In patients with stroke associated with aortic atherosclerotic lesions, we recommend antiplatelet therapy over no therapy (Grade 1A). For patients with cryptogenic stroke associated with mobile aortic arch thrombi, we suggest either oral anticoagulation or antiplatelet agents (Grade 2C).

4.4.4. In patients with cryptogenic ischemic stroke and a patent foramen ovale, we recommend antiplatelet therapy over no therapy (Grade 1A) and suggest antiplatelet agents over anticoagulation (Grade 2A).

4.4.5. In patients with mitral valve strands or prolapse, who have a history of TIA or stroke, we recommend antiplatelet therapy (Grade 1A).

5.1 Anticoagulation for Cerebral Venous Sinus Thrombosis

5.1. In patients with venous sinus thrombosis, we recommend that clinicians use UFH (Grade 1B) or low-molecular-weight heparin (Grade 1B) over no anticoagulant therapy during the acute phase, even in the presence of hemorrhagic infarction. In these patients, we recommend continued use of vitamin K antagonist therapy for up to12 months (target INR, 2.5; range, 2.0–3.0) [Grade 1B].

Ischemic stroke is a syndrome of multiple etiologies and protean clinical manifestations. Atherosclerosis of the arteries, large and small, that supply the brain most commonly causes ischemic stroke. Atherosclerosis of the proximal aorta is also a source of atherogenic brain emboli. Large artery atherosclerotic infarction occurs when there is an impediment to normal perfusion, usually caused by a severe arterial stenosis or occlusion due to atherosclerosis and coexisting thrombosis or artery-to-artery embolism. Microatheroma, lipohyalinosis, and other occlusive diseases of the small penetrating brain arteries are the most frequent causes of small, subcortical “lacunar” infarcts. About 20% of ischemic strokes are due to cardiogenic embolism, most commonly from atrial fibrillation. Overall, about 30% of ischemic strokes remain cryptogenic despite a reasonably thorough evaluation. Cerebral angiography done within a few hours of cryptogenic stroke typically reveals occlusions of intracranial arteries. Most of these occlusions resolve within a few days, suggesting transient embolic or thrombotic obstruction. Thus, the specific pathogenesis of stroke in individual patients is sometimes difficult to elucidate. Table 1 describes the eligibility criteria for the studies considered in each section of the recommendations that follow.

The rationale for thrombolytic therapy is based on the recognition that the majority of ischemic strokes are caused by thrombotic or thromboembolic arterial occlusions.12 Pathologic and angiographic studies demonstrate the presence of occlusive clot in up to 80% of ischemic strokes.1,3 Thrombotic occlusion may also be responsible for a significant number of events in the 20% of patients without angiographic evidence of occlusion as the thrombus may have lysed spontaneously prior to delayed vascular imaging or the infarct may be due to microthrombus resulting in small-vessel occlusions which escape angiographic detection.

The therapeutic window for rescuing ischemic but still viable brain tissue is attainable for many patients but is challengingly brief. Neuronal death and brain infarction evolve progressively in a time-dependent fashion determined by both the duration and severity of the ischemic insult.45 Therapeutic strategies designed to restore cerebral perfusion in a timely fashion have the potential to limit the cellular, biochemical, and metabolic consequences of cerebral ischemia that ultimately lead to irreversible brain injury. The ultimate goal of early reperfusion therapy is to reduce or prevent brain infarction and thereby minimize the long term disability, neurologic impairment, and stroke-related mortality. The 2001 ACCP Guidelines describe the preclinical evidence and the results of early clinical trials of thrombolysis.6Table 2 summaries the results of randomized trials of IV thrombolytic therapies for acute ischemic stroke.

Current Status: The use of IV tissue plasminogen activator (tPA) within the first 3 h of onset of acute ischemic stroke has received regulatory approval in the United States, Canada, Europe, Australia, many Asian countries, as well as several other countries throughout the world. The 1995 landmark report from the National Institute of Neurologic Disorders and Stroke (NINDS) rt-PA Stroke Study Group demonstrated substantial benefit from the careful use of IV tPA in patients with acute ischemic stroke of < 3 h duration.7 This ushered in a new era in acute stroke management requiring that stroke be recognized and treated as a time-critical emergency. Although the approved inclusion/exclusion criteria have slight national or regional variations, most countries have adopted protocols based on the principles utilized in the NINDS studies. Despite the potential benefits of thrombolytic therapy, there are considerable obstacles hindering the widespread use of tPA in routine clinical practice. Thrombolytic therapy for acute stroke poses considerable logistical challenges that require a reengineering of stroke care systems to permit widespread access to this treatment.

Thrombolytic therapy for the treatment of acute ischemic stroke has been the subject of intense investigation. In the past several years nine randomized, placebo-controlled trials have been reported using IV recombinant tissue plasminogen activator (rt-PA), streptokinase (SK), or intraarterial recombinant prourokinase (rpro-UK). Metaanalysis of randomized trials of thrombolytic therapy in acute stroke and pooled-data analysis of randomized placebo-controlled trials of tPA vs placebo provides additional evidence for the use of tPA within 3 h of symptom onset.

Concerns regarding the generalizability of clinical trial results and the safety and efficacy of IV tPA therapy in routine clinical practice have been addressed in large formal phase IV studies that have demonstrated results comparable to the NINDS trials. Finally, numerous case series and registries using protocols derived from the NINDS trials have been generally favorable.

Our current recommendations are based on the clinical trial inclusion criteria of time from symptom onset to treatment and on the accepted importance of early treatment. Differences in fibrin specificity, pharmacokinetic and pharmacodynamic properties prevent the ready extrapolation of trial results with IV tPA to other agents, doses, or routes of administration.

1.1 IV tPA for Acute Ischemic Stroke Within 3 h of Symptom Onset

Metaanalysis Data for Treatment < 3 h: The Cochrane stroke group has evaluated the time to treatment effect for thrombolysis in acute stroke. The main Cochrane metaanalysis includes studies that used either tPA (NINDS, European Cooperative Acute Stroke Study [ECASS], and ECASS II) or SK (MAST-I, MAST-E, and ASK) within the first 3 h after symptom onset. The NINDS trial contributed > 50% of treated patients to this metaanalysis.89 Thrombolytic therapy within 3 h of symptom onset significantly reduced the number suffering the combined end point of death or dependency: 55.2% thrombolytic-treated patients died or were dependent compared with 68.3% of those allocated to control (odds ratio [OR], 0.58; 95% confidence interval [CI], 0.5–0.7; p < 0.0000; absolute risk reduction, 13.1%). There was a nonsignificant excess of deaths in the thrombolysis-treated group 22.3% vs 20.7% in control patients (OR, 1.11; 95% CI, 0.84–1.47). Overall there were 126 fewer dead or dependent stroke patients for every 1,000 thrombolysis-treated patients within 3 h of symptom onset.

The Cochrane metaanalysis restricted to all trials using tPA (NINDS, ECASS I, and ECASS II) and more relevant to current practices demonstrated even more favorable results: 140 fewer dead or dependent per 1,000 tPA-treated patients (OR, 0.55; 95% CI, 0.42–0.72) with a nonsignificant trend toward fewer deaths (OR, 0.92; 95% CI, 0.65 to 1.30).

Pooled Data Analysis: The investigators of the large tPA trials (ATLANTIS A and B, ECASS I and II, and the NINDS trials) conducted a pooled analysis using original individual patient data (n = 2,775) from these six randomized trials comparing IV tPA and control.10 An adjusted multiple logistic regression model demonstrated a relationship between onset-to-treatment time and treatment effect. There was substantial evidence of benefit for tPA therapy delivered within the first 180 min and evidence of declining benefit up to 270 min after symptom onset. Efficacy outcomes were measured utilizing the National Institutes of Health Stroke Scale (NIHSS) as measure of neurologic deficit, the modified Rankin Scale (mRS) as measure of global disability, and the Barthel Index (BI) as measure of independence in activities of daily living. Favorable outcome was defined by the NIHSS, mRS, and BI dichotomized to evaluate minimal or no poststroke disability. The OR for favorable 3-month outcome for patients treated with tPA compared to placebo was 2.8 (95% CI, 1.8–4.5) when tPA was given in the first 90 min, 1.6 (1.1–2.2) for 91–180 min, and 1.4 (1.1–1.9) for 181–270 min. The benefit of IV tPA therapy becomes small and lacks significance (OR, 1.2; 95% CI, 0.9 to 1.5) for patients treated between 271 and 360 min. The rate of clinically significant parenchymal hematoma defined as a dense space-occupying blood clot resulting in early neurologic deterioration or death was 5.9% with tPA compared to 1.1% in placebo-treated patients (p < 0.01). The 90-day mortality rate in patients with symptomatic intracerebral hematoma (ICH) was not significantly associated with onset to treatment time (p = 0.71) or baseline stroke severity (p = 0.10). This analysis demonstrates that earlier treatment is strongly associated with greater benefit and that patients should be treated as quickly as possible. It also suggests that a diminishing small benefit may persist for up to 4.5 h.

Time-to-Treatment Effect: A consistent and powerful time-to-treatment effect on clinical outcome has been demonstrated in both the NINDS study (see below) as well as in the pooled analysis.1011 Outcomes are better with early treatment. The practice implications of this observation are profound. Systems of emergency stroke care must be optimized to provide for rapid patient access, evaluation, imaging, and treatment.

Individual Trials of tPA Within 3 h: Four large-scale trials using different doses, therapeutic windows, and treatment protocols have evaluated IV tPA: the NINDS rt-PA study7 the ECASS-I,12the ECASS II,13and the ATLANTIS rt-PA (Alteplase) Acute Stroke Trial.1415 The 2004 ACCP Guidelines include a detailed summary of these trials16; safety and efficacy data are summarized in Table 2.

Only the NINDS rt-PA study exclusively included patients treated within 3 h of symptom onset and this trial was the only study to clearly demonstrate efficacy on the primary end points.7 In NINDS, the benefits of tPA were consistent regardless of patient age, stroke subtype, stroke severity, or prior use of aspirin. Patients with severe neurologic deficits measured by the baseline NIHSS were less likely to have a good outcome, regardless of treatment. A subgroup analysis of patients ≥ 75 years old with an initial NIHSS of > 20 (20 points is a severe stroke typically presenting with severe motor, sensory, visual, and language or behavioral deficits) demonstrated a reduction in death or severe disability with tPA compared with placebo.17 This overall benefit occurred despite the increased risk of symptomatic ICH in patients with severe strokes (adjusted OR, 4.3; 95% CI, 1.6–11.9).

There were differences in baseline NIHSS scores between tPA-treated and placebo-treated patients in the NINDS study. These differences increased the number of patients with favorable outcomes in the tPA group treated between 91–180 min and reduced favorable outcomes with tPA in the 0–90 min group. Analysis of the NINDS data, adjusted for the baseline NIHSS, demonstrated an effect of onset-to-treatment time for a favorable 3-month outcome: the adjusted OR for a favorable 3-month outcome in tPA-patients treated within the first 90 min was 2.11 (95% CI, 1.33–3.35) compared to 1.69 (95% CI, 1.09–2.62) for patients treated between 91 and 181 min.11 There was no onset-to-time of treatment effect on the incidence of ICH.

A formal independent reanalysis of the NINDS data commissioned to address concerns about the potential impact of baseline variables found that the adjusted tPA to placebo OR of a favorable outcome was 2.1 (95% CI, 1.5–2.9), despite the differences in baseline severity and despite the increased risk of symptomatic ICH.18 The clinical impact of symptomatic ICH is of course integrated into the overall assessment of favorable outcome.

Phase IV Studies: Three large formal prospective Phase IV studies have examined outcomes with use of tPA in NINDS-derived protocols restricted to a 3-h treatment window in clinical practice. The Standard Treatment With Alteplase to Reverse Stroke (STARS) study included 389 patients from 57 medical centers in the United States (24 academic and 33 community).19The Canadian Activase for Stroke Effectiveness Study (CASES) enrolled 1,132 patients at 60 centers in Canada (25 academic and 35 community).20 Both STARS and CASES demonstrated that low rates of symptomatic intracerebral hemorrhage (3.3% in STARS and 4.6% in CASES) could be obtained using tPA in broad clinical practice settings. These studies are reviewed in the 2004 ACCP guidelines.16

The most recent large phase IV trial was the European SITS-MOST Study (Safe Implementation of Thrombolysis in Stroke Monitoring Study).21 This prospective, open, monitored observational cohort study was mandated by the European Agency of Medicinal Products as a condition for permanent licensing of tPA in the European Union. A total of 6,483 patients were treated with IV tPA between 2003 and 2006 making SITS-MOST the largest phase IV study evaluating clinical safety of tPA use in acute ischemic stroke. In addition to conventional NINDS tPA exclusions, SITS-MOST also excluded patients if they were > 80 years of age or if their baseline NIHSS score was > 25 points. The primary outcome measures were symptomatic intracranial hemorrhage (defined as a type 2 parenchymal hematoma exceeding 30% of the infarct area with mass effect combined with clinical worsening of ≥ 4 points on the NIHSS scale) and death. The incidence of symptomatic intracerebral hemorrhage as defined was 1.7%. Applying the Cochrane/NINDS definitions for symptomatic ICH of any bleeding plus any neurologic worsening, the incidence of symptomatic ICH was 7.3% at 7 days. The overall mortality rate was 11.3% compared to 17.3% in the pooled controlled clinical trials data. Although SITS-MOST defined patient eligibility more stringently than either CASES or STARS, this very large study provides considerable reassurances regarding the safety and effectiveness of tPA in clinical practice both in experienced and inexperienced centers.

The results of these three large formal phase IV studies demonstrate that IV tPA can be given with safety and clinical outcomes comparable to those demonstrated in the NINDS trial and with a trend to lower rates of symptomatic ICH. These studies also demonstrated that comparable results were obtained in both academic centers and community hospitals and in both experienced and inexperienced sites providing protocols are in place and adhered to.

Published Reports From Routine Clinical Practice: Published reports of the use tPA in routine clinical experience have generally been favorable with reported rates of symptomatic ICH usually < 7%.2225 The largest multicenter survey of the use of tPA in clinical practice reported a 6% symptomatic ICH rate in 1,205 patients analyzed both retrospectively and prospectively.26 Logistic regression models identified age, stroke severity, elevated glucose, low platelets, and early major CT changes as predictors of symptomatic ICH. Strict adherence to protocols and experience are important to ensure appropriate use and adequate safety. Increased rated of symptomatic ICH associated with protocol violations have been reported by several groups.24,2628 A survey of community experience in 29 Cleveland area hospitals reported a symptomatic ICH rate of 15.7% associated with protocol violations in 50% of the 70 patients.29This exceptionally high rate of ICH underscores the need for close adherence to protocol guidelines and the importance of experience and expertise. A subsequent report from the Cleveland area hospitals has demonstrated that training and better adherence to NINDS-based protocols can result in reduction in the rates of ICH to acceptable levels.30

Resource Implications

A cost-effectiveness analysis based on data from the NINDS trial31concluded that tPA was economically dominant—both more effective and cost saving compared with not using tPA. The cost savings were attributable to reduced length of hospital stay seen for tPA patients in the trial, as well as reduced projected use of rehabilitation and nursing home resources. A similar study, based on the NINDS results for efficacy but using Canadian costs, came to a similar conclusion.32Notably, an extensive analysis for the British National Health Service (NHS) did not support this conclusion.33 The discrepancies were due primarily to differences in the authors’ estimates of treatment efficacy.

A generic analysis of acute stroke treatments suggests that the economic case for tPA—at least for developed countries—does not require that treatment lead to shorter acute hospitalization or dramatic shifts in the distribution of disability.34 Even treatments that are moderately effective (eg, may shift the distribution of Rankin disability by 5%) may be cost-effective from a societal perspective because reduced disability is likely associated with decreased long-term cost, particularly nursing home and home care costs. In developed countries, tPA is comparable in price to a few days of nursing home care. However, in an environment in which long-term care costs are small relative to the cost of tPA, this down-line savings will not be as salient.

Despite a plausible societal case for tPA, this modality has not been widely embraced. Low uptake of tPA may be due, in part, to the cost of making tPA available. These costs include establishing mechanisms for rapid identification, transport, triage, imaging, and initiation of infusion. Even for hospitals that find these barriers to be technically surmountable, the effort required for what is often a small number of eligible patients is not perceived to be good use of resources. Further, the costs of tPA are borne by the acute care hospital, which does not benefit from cost savings due to decreased need for long-term care. Thus the economic case for tPA is compelling only in integrated health systems engaged in the care continuum.35

Recommendation

1.1.1. For eligible patients (see inclusion and exclusion criteria listed below) we recommend administration of IV tPA in a dose of 0.9 mg/kg (maximum of 90 mg), with 10% of the total dose given as an initial bolus and the remainder infused > 60 min, provided that treatment is initiated within 3 h of clearly defined symptom onset (Grade 1A).

Underlying values and preferences: This recommendation places relatively more weight on overall prospects for long-term functional improvement despite the increased risk of symptomatic intracerebral hemorrhage in the immediate peristroke period.

Remark: The following criteria determine eligibility for treatment.

Inclusion Criteria: Age ≥ 18 years, clinical diagnosis of stroke with a clinically meaningful neurologic deficit, clearly defined time of onset of < 180 min before treatment, and a baseline CT showing no evidence of intracranial hemorrhage.

Exclusion Criteria: Minor or rapidly improving symptoms or signs, CT signs of intracranial hemorrhage, a history of intracranial hemorrhage, seizure at stroke onset, stroke or serious head injury within 3 months, major surgery or serious trauma within 2 weeks, GI or urinary tract hemorrhage within 3 weeks, systolic BP > 185 mm Hg, diastolic BP > 110 mm Hg, aggressive treatment required to lower BP, glucose < 50 mg/dL or > 400 mg/dL, symptoms of subarachnoid hemorrhage, arterial puncture at a noncompressible site or lumbar puncture within 1 week, platelet count < 100,000/mm3, heparin therapy within 48 h associated with elevated activated partial thromboplastin time, clinical presentation suggesting post-myocardial infarction pericarditis, pregnant women, anticoagulation due to oral anticoagulants (international normalized ratio [INR] > 1.7).

Recommendation