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Clinical Policy: Use of Intravenous tPA for the Management of Acute Ischemic Stroke in the Emergency Department

DRAFT January 5, 2015

From the American College of Emergency Physicians Clinical Policies Subcommittee (Writing Committee) on Use of Intravenous tPA for Ischemic Stroke:

Michael D. Brown MD, MSc (Subcommittee Chair)

John H. Burton, MD

Devorah J. Nazarian, MD

Susan B. Promes, MD, MBA

_________________________________________________________________________________________

Members of the American College of Emergency Physicians Clinical Policies Committee (Oversight Committee):

Stephen V. Cantrill, MD (Interim Chair 2014)

Michael D. Brown, MD, MSc (Chair 2014-2015)

Deena Brecher, MSN, RN, APN, ACNS-BC, CEN, CPEN (ENA Representative 2014-2015)

Deborah B. Diercks, MD, MSc

Seth R. Gemme, MD

Charles J. Gerardo, MD, MHS

Steven A. Godwin, MD

Sigrid A. Hahn, MD

Benjamin W. Hatten, MD, MPH

Jason S. Haukoos, MD, MSc (Methodologist)

Amy Kaji, MD, MPH, PhD (Methodologist)

Bruce M. Lo, MD, CPE, RDMS

Sharon E. Mace, MD

Devorah J. Nazarian, MD

Mark C. Pierce, MD (EMRA Representative 2014-2015)

Susan B. Promes, MD, MBA

Kaushal Shah, MD

Richard D. Shih, MD

Scott M. Silvers, MD

Michael D. Smith, MD, MBA

Christian A. Tomaszewski, MD, MS, MBA

Jonathan H. Valente, MD

Stephen P. Wall, MD, MSc, MAEd (Methodologist)

Stephen J. Wolf, MD

Robert E. O’Connor, MD, MPH (Board Liaison 2010-2014)

ABSTRACT

This clinical policy from the American College of Emergency Physicians (ACEP) is the revision of a 2012 clinical policy evaluating critical questions in the evaluation and management of patients with acute ischemic stroke.1 A writing subcommittee conducted a systematic review of the literature to derive evidence-based recommendations to answer the following clinical questions: (1) Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset? (2) Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset? Evidence was graded and recommendations were made based on the strength of the available data.

INTRODUCTION

Stroke is a leading cause of death in the United States with approximately 800,000 new strokes documented each year.2,3 Among survivors, stroke often results in disability, reducing mobility in half of those age 65 years or older.2 In 1996, the Food and Drug Administration (FDA) approved intravenous (IV) tissue plasminogen activator (tPA) as a treatment for acute ischemic stroke. Despite approval by the FDA, the use of IV tPA for stroke has been polarizing4 and continues to generate a large volume of published literature.

The last ACEP clinical policy addressing the use of IV tPA for acute ischemic stroke was approved in 2012.1 Since then, changes to the ACEP clinical policies development process have been implemented (ACEP’s clinical policy development process can be found at http:clinicalpolicies), the grading forms used to rate published research have continued to evolve, and newer research articles have been published.

The 2012 IV tPA clinical policy recommendation to “offer” tPA to patients presenting with acute ischemic stroke within 3 hours of symptom onset was consistent with other national guidelines (eg, American Heart Association5 and the American College of Chest Physicians6). Unfortunately, the essence of the term “offer” may have been lost to readers and has therefore been avoided in this revision.

As in the previous ACEP clinical policy,1 the two critical questions addressed in this clinical policy were: (1) Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset? (2) Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?

METHODOLOGY

This clinical policy was created after careful review and critical analyses of the medical literature and was based on a systematic review of the literature. Searches of MEDLINE, MEDLINE InProcess and other nonindexed citations portion of MEDLINE, and the Cochrane Database were performed. All searches were limited to English-language sources, human studies, and adults, from January 2011 to September 2014; searches were conducted on January 27, 2014 and September 3, 2014. Specific key words/phrases and years used in the searches are identified under each critical question.

Study Selection: 1,765 references were identified in the updated literature search as potentially relevant to the critical questions (992 in the search on January 27, 2014 and 773 in the search on September 3, 2014). From these, 136 articles were selected from the January 27, 2014 search, and 59 articles from the September 3, 2014 search, resulting in a total of 195 new articles for full-text review.

Additionally, given recent changes to the ACEP clinical policy development process, articles rated as Class I or II in the 2012 policy1 were also reviewed and graded by the committee methodologists using current grading forms (available at clinicalpolicies). Finally, relevant articles from the bibliographies of included studies and more recent articles identified by committee members and reviewers were also included.

This policy is a product of the ACEP clinical policy development process and is based on the existing literature; when literature was not available, consensus of emergency physicians was used. Clinical policies are scheduled for revision every 3 years; however, interim reviews such as this revision are conducted when technology, methodology, or the practice environment changes significantly. ACEP was the funding source for this clinical policy.

Assessment of Classes of Evidence

All articles used in the formulation of this clinical policy were graded by at least 2 committee members or methodologists; all Class I and Class II articles were graded by at least two methodologists. Each article was assigned a design class with design 1 representing the strongest study design and subsequent design classes (eg, design 2, design 3) representing respectively weaker study designs for therapeutic, diagnostic, or prognostic clinical reports, or meta-analyses (Appendix A). Articles were then graded on dimensions related to the study’s methodological features, such as randomization processes, blinding, allocation concealment, methods of data collection, outcome measures and their assessment, selection and misclassification biases, sample size, and generalizability. Using predetermined formulas related to the study’s design, methodological quality, and applicability to the critical question, articles received a final Class of Evidence grade (ie, Class I, Class II, Class III, or Class X) (Appendix B). Articles identified with fatal flaws or that were ultimately not applicable to the critical question received a Class of Evidence grade “X” and were not used in formulating recommendations for this policy. Grading was done with respect to the specific critical questions; thus, the level of evidence for any one study may vary according to the question for which it is being considered. As such, it was possible for a single article to receive different Classes of Evidence as different critical questions were answered from the same study. Question-specific Classes of Evidence grading can be found in the Evidentiary Table included at the end of this policy.

Translation of Classes of Evidence to Recommendation Levels

Strength of recommendations regarding each critical question were made by subcommittee members using results from strength of evidence grading, expert opinion, and consensus among subcommittee members according to the following guidelines:

Level A recommendations. Generally accepted principles for patient care that reflect a high degree of clinical certainty (ie, based on evidence from 1 or more Class of Evidence I or multiple Class of Evidence II studies).

Level B recommendations. Recommendations for patient care that may identify a particular strategy or range of strategies that reflect moderate clinical certainty (ie, based on evidence from 1 or more Class of Evidence II studies or strong consensus of Class of Evidence III studies).

Level C recommendations. Recommendations for patient care that are based on evidence from Class of Evidence III studies or, in the absence of any adequate published literature, based on expert consensus. In instances where consensus recommendations are made, “consensus” is placed in parentheses at the end of the recommendation.

There are certain circumstances in which the recommendations stemming from a body of evidence should not be rated as highly as the individual studies on which they are based. Factors such as heterogeneity of results, uncertainty about effect magnitude and consequences, and publication bias, among others, might lead to such a downgrading of recommendations.

For this policy, recommendations were based on one Class I randomized controlled trial, 4 Class II articles, and 29 Class III studies for question 1. Recommendations were based on one Class II randomized controlled trial, and 41 Class III studies for question 2.

When possible, clinically oriented statistics (eg, likelihood ratios, number needed to treat [NNT]) are presented to help the reader better understand how the results may be applied to the individual patient. For a definition of these statistical concepts, see Appendix C.

This policy is not intended to be a complete manual on the evaluation and management of patients with acute ischemic stroke but rather a focused examination of critical issues that have particular relevance to the current practice of emergency medicine.

It is the goal of the Clinical Policies Committee to provide an evidence-based recommendation when the medical literature provides enough quality information to answer a critical question. When the medical literature does not contain adequate empirical data to answer a critical question, the members of the Clinical Policies Committee believe that it is equally important to alert emergency physicians to this fact.

This clinical policy is not intended to represent a legal standard of care for emergency physicians. Recommendations offered in this policy are not intended to represent the only diagnostic or management options available to the emergency physician. ACEP recognizes the importance of the individual physician’s judgment and patient preferences. This guideline defines for the physician those strategies for which medical literature exists to provide support for answers to the critical questions addressed in this policy.

Scope of Application. This guideline is intended for physicians working in emergency departments (EDs).

Inclusion Criteria. This guideline is intended for adult patients aged 18 years and older presenting to the ED with acute ischemic stroke.

Exclusion Criteria. This guideline is not intended to be used in pediatric patients or pregnant patients.

A summary of potential benefits and harms of implementing the recommendations is presented in Appendix D.

CRITICAL QUESTIONS

1. Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?

Patient Management Recommendations

Level A recommendations. The increased risk of symptomatic intracerebral hemorrhage (approximately 7% compared to a baseline of 1%) must be considered when deciding whether to administer IV tPA to acute ischemic stroke patients.

Level B recommendations. With a goal to improve functional outcomes, IV tPA may be given to carefully selected acute ischemic stroke patients within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication.

Level C recommendations. Shared decision-making between the patient (and/or their surrogate) and a member of the healthcare team must include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA for acute ischemic stroke. (Consensus recommendation)

Key words/phrases for literature searches: Stroke, cerebrovascular accident, thrombolytic, tPA, thrombolytic therapy, drug therapy, emergency department or emergency room, emergency service, hospital, and variations and combinations of the key words/phrases.

A study was considered directly applicable if IV tPA was administered within the specified timeframe (ie, within 3 hours of symptom onset). To be included, articles were required to report patient-centered outcomes such as symptomatic intracerebral hemorrhage (sICH), mortality, or a validated measure for functional outcome. In terms of assessing the potential benefits of IV tPA, the subcommittee focused on the modified Rankin Scale (mRS) since it is both patient-centered and consistently reported1,7 (Table). An “excellent” functional outcome is typically equated to a score of 0 to 1 on the mRS; a score of 2 is considered a “good” functional outcome; and a score of 3 to 6 is considered “poor” functional outcome. To place this into context, a mRS score of 2 is defined as a slight disability that allows the patient to look after their affairs without assistance, yet unable to perform some previous activities (eg, drive a car, dance).7

Table. Modified Rankin Scale.* (Used with permission).

Score Description

0 No symptoms

1 No significant disability despite symptoms; able to carry out all usual duties and activities

2 Slight disability; unable to carry out all previous activities but able to look after own affairs without assistance

3 Moderate disability; requiring some help but able to walk without assistance

4 Moderately severe disability; unable to walk without assistance and unable to attend to own bodily needs without assistance

5 Severe disability; bedridden, incontinent, and requiring constant nursing care and attention

6 Dead

Rankin J. Cerebral vascular accidents in patients over the age of 60. II. Prognosis. Scott Med J. 1957;2:200-215. © Copyright 1957 Royal Society of Medicine Press, UK.

*The modified Rankin Scale is a 6-point clinical outcome scale that measures a patient’s function and independence. A lower score indicates a better outcome.

The major harm associated with IV tPA therapy in this clinical setting is sICH, defined as bleeding associated with “any decline in neurological status” per the National Institute of Neurological Disorders and Stroke (NINDS) trials8 and, when it occurs, sICH is ultimately associated with a substantial increase in the risk of an unfavorable outcome (mRS 3 to 6).9 Studies have used varying definitions for sICH, such as those requiring a deterioration of 4 or more points on the National Institutes of Health Stroke Scale (NIHSS)9 (Figure 1). When possible, the subcommittee reported results using the more inclusive NINDS definition.

Figure 1. National Institutes of Health Stroke Scale.

Level of consciousness 1a–1c:

1a. Alertness

0=alert and responsive

1=arousable to minor stimulation

2=arousable only to painful stimulation

3=reflex responses or unarousable

1b. Orientation: Ask the patient his or her age and the

month; answers must be exact.

0=Both correct

1=One correct (or dysarthria, intubated, foreign language)

2=Neither correct

1c. Commands: Ask the patient to open/close eyes and to

grip/release the nonparetic hand (or other 1-step command).

Grip and release nonparetic

0=Both correct (OK if impaired by weakness)

1=One correct

2=Neither correct

2. Best Gaze: Only horizontal eye movements are checked

by voluntary movement or reflective movement (doll’s

eyes, not by calorics).

0=Normal

1=Partial gaze palsy

2=Forced eye deviation or total paresis that cannot be

overcome by doll’s eyes

3. Visual Field: Test using confrontation (or visual threat if

necessary).

0=No visual loss

1=Partial hemianopia, quadrantanopia, extinction

2=Complete hemianopia

3=Bilateral hemianopia or blindness (including cortical

blindness)

4. Facial Palsy: If stuporous, check symmetry of grimace

to pain.

0=Normal

1=Minor paralysis, flat nasolabial fold or asymmetric smile

2=Partial paralysis (lower face)

3=Complete paralysis (upper and lower face)

5. Motor Arm: arms outstretched 90 degrees (patient

sitting) or 45 degrees (patient supine) for 10 seconds.

Encourage patient for best effort. Assess both sides.

0=No drift for full 10 seconds

1=Drift but does not hit bed

2=Some antigravity effort but cannot sustain

3=No antigravity effort, but even minimal movement

counts

4=No movement at all

6. Motor Leg: Raise leg to 30 degrees and hold for 5

seconds; test both sides.

0=No drift for full 5 seconds

1=Drift but does not hit bed

2=Some antigravity effort but cannot sustain

3=No antigravity effort, but even minimal movement

counts

4=No movement at all

X=Unable to assess because of amputation, fusion,

fracture, etc.

7. Limb Ataxia: Check finger to nose and heel to shin on both sides (ataxia is scored only if out of proportion to weakness).

0=No ataxia (or aphasic, hemiplegic)

1=Ataxia in 1 limb

2=Ataxia in 2 limbs

X=Unable to assess because of amputation, fusion,

fracture, etc.

8. Sensory: Use safety pin.

Check grimace or withdrawal if stuporous. Score only

stroke-related losses.

0=Normal

1=Mild to moderate unilateral loss but patient aware of

touch (or aphasic, confused)

2=Total loss, patient unaware of touch, coma, bilateral loss

9. Best Language: Describe cookie jar picture, name

objects, and read sentences (these standard items can be

found on the Internet and at the American Heart Association

Web site).

0=Normal

1=Mild to moderate aphasia (partly comprehensible)

2=Severe aphasia (almost no information exchanged)

3=Mute, global aphasia, coma

10. Dysarthria: Read list of words.

0=Normal

1=Mild to moderate, slurred but intelligible

2=Severe, unintelligible or mute

X=Intubation or mechanical barrier

11. Extinction/Inattention: Simultaneously touch patient

on both hands, show fingers in both visual fields, ask

whether patient recognizes own left hand.

0=Normal, none detected (visual loss alone)

1=Neglects or extinguishes to double simultaneous

stimulation in any modality (visual, auditory, sensory, spatial, or body parts)

2=Profound neglect in more than 1 modality, does not

recognize own hand

X=Unable to assess because of amputation, fusion, fracture, etc.

The NIHSS is an 11-part scale that measures the neurologic examination in a codified manner. The scale ranges from 0 to 42. A score of less than 5 indicates a small stroke, and greater than 20 indicates a large stroke. Physicians can learn to perform the NIHSS on a training module on the Internet. Standard pictures (eg, the cookie jar picture) and lists of words can also be downloaded from the Internet.

Potential Benefits

It has been nearly 20 years since the last patient was enrolled in part II of the tPA for acute stroke trials sponsored by the NINDS. This trial provided the scientific basis for the FDA’s approval of the use of IV tPA in acute stroke.8 The results of the NINDS trials (Class I) demonstrated an absolute difference of 16% with respect to excellent functional outcomes (ie, 43% with mRS 0 to 1 for tPA versus 27% for control), thus rendering a NNT of 6; 95% CI 4 to 11. Although the enrollment criteria for the NINDS trials (Figure 2) required a measurable deficit on the NIHSS, there was a paucity of patients presenting with mild stroke (NIHSS score 2 to 4).10 In an effort to address the current state of equipoise for IV tPA in patients presenting with mild (NIHSS score 0 to 4) or rapidly improving symptoms, a randomized controlled trial is actively enrolling subjects.11 Recognizing the limited data for those presenting with mild stroke or profound deficits (ie, NIHSS score greater than 22), the use of IV tPA within 3 hours of symptom onset is approved by the FDA for selected patients without contraindications (Figure 2).

Data from the NINDS trials continue to be reanalyzed.10,12-14 Despite inherent problems with post-hoc reanalyses,15 these Class II and Class III publications10,12-14 elucidate many of the strengths and limitations of the NINDS trials. Although strict randomization was followed in the NINDS trials, there was an imbalance in baseline stroke severity scores between the intervention and control groups.12,13 The original NINDS trials reported a median baseline NIHSS score of 14 for those randomized to tPA, and 15 for the control group.8 Importantly, a subsequent reanalysis of the original NINDS dataset showed a larger proportion of patients with milder strokes with a NIHSS score of 0 to 5 (19% versus 4%) at 91 to 180 minutes were randomized to tPA.13 Lastly, despite the fact that a majority of tPA-eligible stroke patients presented more than 90 minutes after symptom onset, the NINDS trials were designed to enroll half of their subjects within 90 minutes of symptom onset, which has raised questions about the generalizability of their findings.16

Figure 2. NINDS and ECASS III inclusion and exclusion criteria for intravenous tPA for acute ischemic

stroke.

NINDS Criteria8

Inclusion:

Acute ischemic stroke with clearly defined time

of onset (who could be treated 185 mm Hg or diastolic BP >100

mm Hg

Rapidly improving or minor symptoms

Symptoms suggestive of subarachnoid

hemorrhage

Gastrointestinal or genitourinary hemorrhage

within the previous 21 days

Arterial puncture at a noncompressible site

within the previous 7 days

Seizure at onset of stroke

Use of anticoagulation:

patients receiving heparin within the 48

hours preceding the onset of stroke who have an

elevated PTT,

patients with a PT >15 seconds (or INR

>1.6),

patients with a platelet count 80 years

Severe stroke (NIHSS score >25) or by appropriate

imaging techniques (defined as >1/3 of the

middle cerebral artery territory)

Combination of previous stroke and diabetes

mellitus

Any oral anticoagulant use (regardless of INR

or PT).

*Exclusions (or cautions) to tPA use that

were not specifically mentioned in either

study but are generally used:

Myocardial infarction within previous 3 months

(AHA 2007 guidelines)

Pregnancy and early postpartum period

Known bleeding diathesis, recent pericarditis, recent

lumbar puncture (Brain Attack Coalition

,

accessed December 14, 2014).

AHA, American Heart Association; BP, blood pressure; CT, computed tomography; ECASS, European Cooperative Acute Stroke Study; INR, International Normalized Ratio; NIHSS, National Institutes of Health Stroke Scale; NINDS, National Institute of Neurological Disorders and Stroke; PT, prothrombin time; PTT, partial thromboplastin time; tPA, tissue plasminogen activator.

The only other randomized controlled trial (Class II) that directly addressed the critical question enrolled subjects within 6 hours of stroke symptom onset using block randomization stratified by 0 to less than 3 hours and 3 to 6 hours.17 This study did not show benefit for tPA administered within 6 hours of symptom onset (the primary analysis) and the difference in the subgroup randomized to less than 3 hours (42% with mRS score 0 to 2 for tPA versus 38% for placebo) did not reach statistical significance (OR=1.2; 95% CI 0.6 to 2.3).

A Class III open-label clinical trial, IST-3, by Sandercock et al,18 enrolled patients within 6 hours of symptom onset. In this trial, patients did not meet the standard European Union license-approved protocol for IV tPA; a large percentage of patients were elderly (53% older than 80 years), had elevated systolic blood pressure (34% greater than 165 mm Hg), or had low baseline NIHSS scores (20% with scores 0 to 5). Because of slow enrollment, the trial was stopped early. Among the prespecified subgroups of subjects randomized at less than 3 hours of symptom onset (N=849), the tPA group achieved better functional outcomes compared to controls (31% with good functional outcomes for tPA versus 23% for controls; OR=1.64; 95% CI 1.03 to 2.62) resulting in a NNT of 13; 95% CI 7 to 51.

The literature search also identified an updated meta-analysis (Class III) of randomized control trials for IV tPA.19 The pooled results of the prespecified subgroup analysis for treatment within 3 hours demonstrated benefit in terms of a good functional outcome with thrombolysis (OR=1.53; 95% CI 1.26 to 1.86). Although the authors of the meta-analysis concluded that the 12 studies analyzed were at low risk of bias, a sensitivity analysis based on the methodological and quality differences was not performed. The trial contributing the largest proportion of patient data to the pooled estimate of effect (ie, Sandercock et al IST-318) was rated Class III by the subcommittee, which was one of the factors resulting in a downgrade of the meta-analysis.19 Another Class III meta-analysis based on individual patient-level data reported a similar effect size for tPA administered within 3 hours of symptom onset (OR=1.75; 95% CI 1.35 to 2.27).20

Although efficacy estimates in observational studies are often flawed, these studies may provide information on safety. Among the many registry studies identified in the updated searches, methodological limitations such as selection bias (eg, eligible patients missed or purposely not enrolled in a registry) and measurement bias (eg, mRS assessed by research assistant telephone follow-up rather than an in-person interview by a neurologist) typically resulted in downgrading to Class III or Class X. The search identified a few randomized controlled trials comparing new interventions to standard IV tPA (serving as the control group), which provided data on safety and functional outcomes similar to prospective cohort studies. In summary, numerous Class III studies report prevalences of excellent functional outcomes (mRS 0 to 1) with administration of IV tPA within 3 hours of symptom onset ranging from 37% to 53%.21-31 However, it must be emphasized that registries typically included patients with less severe strokes (baseline mean or median NIHSS scores ranging from 11 to 13) compared to those enrolled in the NINDS trials.

Potential Harms

The NINDS trials8 (Class I) demonstrated an absolute increase in the prevalence of sICH of 6% (ie, sICH=7% for tPA versus 1% for control), thus indicating a number needed to harm [NNH] of 17; 95% CI 12 to 34. The Class III meta-analysis by Wardlaw et al19 reported a pooled estimate for sICH of 8% for tPA versus 1% for controls (OR=4.55; 95% CI 2.92 to 7.09); however, the definition for sICH varied among the included individual trials. Among Class III cohort studies, prevalences of sICH were remarkably consistent when based on the NINDS definition (approximately 7%).28,30-38 As expected, reported rates of sICH are lower in studies that used standard doses of tPA and a definition requiring a deterioration of 4 or more points on the NIHSS (range of 4% to 6% for sICH).23,25,26,34,39-43

In the NINDS trials,8 there was no statistically significant difference in 3-month mortality (17% for tPA versus 21% for control; OR=0.81; 95% CI 0.54 to 1.21). Similarly, 2 Class III meta-analyses reported no difference in mortality for those treated with IV tPA within 3 hours of symptom onset: Wardlaw et al19 (OR=0.91; 95% CI 0.73 to 1.13) and Emberson et al20 (OR=1.00; 95% CI 0.81 to 1.24). According to another Class III meta-analysis by Wardlaw et al44 that included trials using tPA and other thrombolytic agents, there was again no difference in mortality when given within 3 hours of stroke onset (OR 0.99; 95% CI 0.82 to 1.21). Among the Class III cohort studies, there was substantial variability in the reported mortality prevalences, ranging from 1% to 24%.22-26,28-32,35,39,45

Appendix D contains information on key risk-benefit concepts.

2. Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?

Patient Management Recommendations

Level A recommendations. None specified.

Level B recommendations. Despite the known risk of symptomatic intracerebral hemorrhage and the variability in the degree of benefit in functional outcomes, IV tPA may be given to carefully selected acute ischemic stroke patients within 3 to 4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication.

Level C recommendations. Shared decision-making between the patient (and/or their surrogate) and a member of the healthcare team must include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA to ischemic stroke patients between 3 to 4.5 hours after symptom onset. (Consensus recommendation)

Key words/phrases for literature searches: Stroke, cerebrovascular accident, thrombolytic, tPA, thrombolytic therapy, drug therapy, emergency department or emergency room, emergency service, hospital, and variations and combinations of the key words/phrases.

Potential Benefits

The Class II study, (ECASS III – Figure 2), by Hacke et al46 demonstrated improvement in the prevalence of excellent functional outcomes (mRS score 0 to 1) with IV tPA administered within 3 to 4.5 hours after symptom onset (52% for tPA versus 45% for controls; OR=1.34; 95% CI 1.02 to 1.76; NNT=14; 95% CI 7 to 244).

The Class III open-label clinical trial (IST-3) by Sandercock et al18 enrolled patients not meeting the standard European Union approved protocol for IV tPA as discussed under critical question 1 above. In the 3 to 4.5 hour subgroup (N=1,177), there was no statistically significant difference in functional outcomes in those randomized to the tPA arm (32% with good functional outcome in the tPA group versus 38% in the control group [OR=0.73; 95% CI 0.50 to 1.07]). An older Class III randomized trial also showed no difference in 90-day functional outcomes between the tPA and control groups.47 A Class III individual patient data meta-analysis by the Stroke Thrombolysis Trialists’ Collaborative Group20 that pooled data from multiple trials reported an effect size similar to ECASS III (OR=1.26; 95% CI 1.05 to 1.51) for the 3 to 4.5 hour subgroup. Among the Class III observational studies, there was wide variability in terms of baseline stroke severity (mean NIHSS scores ranged from 5 to 17) making comparisons difficult.28,31,32,34,48-62

Potential Harms

The Class II study by Hacke et al46 reported sICH prevalence of 8% for tPA versus 4% for placebo (OR=2.38; 95% CI 1.25 to 4.52; NNH=23; 95% CI 13 to 78); there was no difference in mortality between the two groups. This trial enrolled patients with less severe strokes in comparison to the NINDS trials, which may partly explain why the NNH was higher than that estimated based on the NINDS trials. The Class III individual patient data meta-analysis also reported no difference in mortality for the 3 to 4.5 hour subgroup (OR=1.14; 95% CI 0.95 to 1.36).20 Among other Class III studies,28,31,32,36,44,50,51,53,56,61,63-72 the prevalences of sICH associated with IV tPA administration within 4.5 hours ranged from 4% to 8% when based on the NINDS definition, whereas the prevalence was lower (2% to 6%) for those studies using a sICH definition requiring a change of 4 or more on the NIHSS.34,48,49,52,55,57-60,62,73-77

Future Research

Further research is needed to refine estimates for the effectiveness and safety of IV tPA across the entire acute stroke population (ie, heterogeneity of treatment effect) so that clinicians and patients can have a more informed conversation regarding who is most likely to benefit from the administration of IV tPA, and clinicians can better identify those individuals at highest risk for sICH and other complications.78-80 There is some evidence to suggest that lower weight-based doses of tPA may be effective and result in fewer adverse outcomes, warranting further studies in this area.21,70,77,81 Advancement in individualized medicine (genetics) and more accurate assessment of patient weight may play a role in deciphering the appropriate treatment of stroke patients. High-quality trials are also needed to determine when other interventions (eg, endovascular procedures) or other agents should be used with or without systemic IV tPA.82-84

Relevant industry relationships: There were no relevant industry relationships disclosed by the subcommittee members.

Relevant industry relationships are those relationships with companies associated with products or services that significantly impact the specific aspect of disease addressed in the critical question.

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_____________

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________________

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48. Ebinger M, Scheitz JF, Kufner A, et al. MRI-based intravenous thrombolysis in stroke patients with unknown time of symptom onset. Eur J Neurol. 2012;19:348-350.

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50. Paliwal PR, Ahmad A, Shen L, et al. Persistence of hyperdense middle cerebral artery sign on follow-up CT scan after intravenous thrombolysis is associated with poor outcome. Cerebrovasc Dis. 2012;33:446-452.

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Appendix A. Literature classification schema.*

| | | | |

|Design/ |Therapy† |Diagnosis‡ |Prognosis§ |

|Class | | | |

| | | | |

|1 |Randomized, controlled trial or meta-analysis |Prospective cohort using a criterion |Population prospective cohort or |

| |of randomized trials |standard or meta-analysis of |meta-analysis of prospective |

| | |prospective studies |studies |

| | | | |

|2 |Nonrandomized trial |Retrospective observational |Retrospective cohort |

| | | |Case control |

| | | | |

|3 |Case series |Case series |Case series |

| |Case report |Case report |Case report |

| |Other (eg, consensus, review) |Other (eg, consensus, review) |Other (eg, consensus, review) |

*Some designs (eg, surveys) will not fit this schema and should be assessed individually.

†Objective is to measure therapeutic efficacy comparing interventions.

‡Objective is to determine the sensitivity and specificity of diagnostic tests.

§Objective is to predict outcome, including mortality and morbidity.

Appendix B. Approach to downgrading strength of evidence.

_______________________________________________________

Design/Class

_______________________________

Downgrading 1 2 3

None I II III

1 level II III X

2 levels III X X

Fatally flawed X X X

____________________________________________________________________________________

Appendix C. Likelihood ratios and number needed to treat.*

|LR (+) |LR (-) | |

|1.0 |1.0 |Does not change pretest probability |

|1-5 |0.5-1 |Minimally changes pretest probability |

|10 |0.1 |May be diagnostic if the result is concordant with pretest probability |

|20 |0.05 |Usually diagnostic |

|100 |0.01 |Almost always diagnostic even in the setting of low or high pretest |

| | |probability |

LR, likelihood ratio.

*Number needed to treat (NNT): number of patients who need to be treated to achieve 1

additional good outcome; NNT=1/absolute risk reductionx100, where absolute risk reduction is the risk difference between 2 events (ie, experimental and control groups).

Appendix D. Potential benefits and harms of implementing the recommendations.

1. Is IV tPA safe and effective for acute ischemic stroke patients if given within 3 hours of symptom onset?

Patient Management Recommendations

Level A recommendations. The increased risk of symptomatic intracerebral hemorrhage (approximately 7% compared to a baseline of 1%) must be considered when deciding whether to administer IV tPA to acute ischemic stroke patients.

Level B recommendations. With a goal to improve functional outcomes, IV tPA may be given to carefully selected acute ischemic stroke patients within 3 hours after symptom onset at institutions where systems are in place to safely administer the medication.

Level C recommendations. Shared decision-making between the patient (and/or their surrogate) and a member of the healthcare team must include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA for acute ischemic stroke. (Consensus recommendation)

Potential Benefit of Implementing the Recommendations: Administration of IV tPA within 3 hours of stroke symptom onset increases the probability of better long-term functional outcome (NNT=6; 95% CI 4 to 110 when based on data from the Class I NINDS8 trials).

Potential Harm of Implementing the Recommendations: Administration of IV tPA within 3 hours of stroke symptom onset increases the risk of early sICH (NNH=17; 95% CI 12 to 34 when based on data from the Class I NINDS8 trials).

When considering administration of IV tPA for an acute ischemic stroke patient within 3 hours of stroke symptom onset, the physician and patient (and/or the surrogate), should weigh the potential benefit in terms of long-term functional outcome against the increased risk of sICH while recognizing that IV tPA does not alter 90-day mortality.

Shared decision-making relies on a combination of the best available research evidence, the clinical expertise of the providers, and the unique attributes of the patient and the patient’s family.85-87 Patients tend to overestimate the benefits and underestimate the harms associated with medical interventions88; therefore, it is suggested that patient decision aids be used to improve decision quality.85 Graphic risk communication tools such as person icon arrays have been developed for IV thrombolysis decisions in acute ischemic stroke.89,90 Although these tools rely on group-level data from clinical trials rather than providing dynamic individualized estimates of risk, they may provide a starting point for shared decision-making.

2. Is IV tPA safe and effective for acute ischemic stroke patients treated between 3 to 4.5 hours after symptom onset?

Patient Management Recommendations

Level A recommendations. None specified.

Level B recommendations. Despite the known risk of symptomatic intracerebral hemorrhage and the variability in the degree of benefit in functional outcomes, IV tPA may be given to carefully selected acute ischemic stroke patients within 3 to 4.5 hours after symptom onset at institutions where systems are in place to safely administer the medication.

Level C recommendations. Shared decision-making between the patient (and/or their surrogate) and a member of the healthcare team must include a discussion of potential benefits and harms prior to the decision whether to administer IV tPA to ischemic stroke patients between 3 to 4.5 hours after symptom onset. (Consensus recommendation)

Potential Benefit of Implementing the Recommendations: Administration of IV tPA for ischemic stroke patients within 3 to 4.5 hours of stroke symptom onset may increase the probability of better long-term functional outcome (NNT=14; 95% CI 7 to 244 when based on data from the Class II ECASS III46 trial).

Potential Harm of Implementing the Recommendations: Administration of IV tPA for ischemic stroke patients within 3 to 4.5 hours of stroke symptom increases the risk of early sICH (NNH=23; 95% CI 13 to 78 when based on data from the Class II ECASS III46 trial).

When considering administration of IV tPA for an ischemic stroke patient within 3 to 4.5 hours of stroke symptom onset, the physician and patient (and/or the surrogate), should weigh the potential benefit in terms of long-term functional outcome against the increased risk of sICH.

Evidentiary Table.

|Study and Year |Class of |Setting and Study |Methods and Outcome Measures |Results |Limitations and Comments |

|Published |Evidence |Design | | | |

|NINDS rt-PA Stroke |I |Multicenter |Adults with stroke measurable on the |Part 1: N=291 (144 tPA); part 2: N=333 |Genentech supplied and distributed both the tPA and |

|Study Group8 (1995)|(for Q1) |randomized |NIHSS, CT without evidence of ICH; |(168 (tPA); no significant difference |the placebo and was involved in monitoring the |

| | |controlled trial |double-blinded, placebo controlled; 2 |between tPA (47%) and placebo (30%) |clinical sites; imbalances noted in baseline NIHSS |

| | | |arms: tPA 0.9 mg/kg (maximum 90 mg) |groups in percentages of patients with |scores in the 91 to 180 min treatment stratum; placebo|

| | | |versus placebo with standard care |neurologic improvement at 24 h; at 3 mo |with lower percent in the 0 to 5 category (19% tPA |

| | | |stratified by |the global odds for a favorable outcome |versus 4% placebo) and higher percent in the >20 (18% |

| | | | ................
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