				Using the search form

CAT CLINIC

Charles DiMaggio, PA-C, MPH
DEPARTMENT EDITOR

Critically appraised topics: Using evidence-based medicine to answer clinical questions

Is rt-PA useful for stroke after 3 hours?

Jeremy P. Nau, PA-C

Mr. Nau practices cardiology at Cardiovascular Medicine in Marietta, Ga. Dr. DiMaggio is an epidemiologist with the Nassau County Department of Health, Mineola, NY, and a member of the editorial board of JAAPA.

Case: Hemiparesis and dysarthria

A 76-year-old woman arrived at the emergency department approximately 4 hours after the abrupt onset of right-side weakness and difficulty speaking. Rapid primary and secondary assessments revealed a stable patient experiencing acute stroke syndrome. Appropriate laboratory studies, an ECG, and chest radiographs were obtained, in addition to a noncontrast CT study of the head. Acute brain hemorrhage and early signs of major neuronal infarction were ruled out, and a neurologist was consulted regarding the use of IV thrombolytics. Current medications included a baby aspirin daily, a statin, and an anti-inflammatory drug.

Clinical question

Recombinant tissue plasminogen activator (rt-PA) is currently indicated in acute ischemic stroke within 3 hours of symptom onset.^1-3 Is the use of this drug safe and effective beyond the 3-hour mark?

Search criteria

Search parameters were narrowed to articles that discussed the use of rt-PA beyond 3 hours; functional outcome assessment based on the modified Rankin Scale (mRS—a numeric scale that reflects the degree of disability ranging from none [0] to death [6]) 90 days after treatment; and data published after the National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study. The NINDS trial was the first study to unequivocally demonstrate reduced rates of death and disability in stroke patients who received rt-PA, despite a significantly increased incidence of symptomatic intracranial hemorrhage (ICH) in the rt-PA group (6.4% vs 0.6%, P ,.001).^4,5

Search results

(1) Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: A randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic Stroke. JAMA. 1999;282:2019-2026.

(2) Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS [ECASS I]). JAMA. 1995;274:1017-1025.

(3) Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245-1251.

Evaluating the evidence

All studies required a baseline CT scan to exclude ICH. ECASS I, ECASS II, and ATLANTIS also established CT exclusion criteria such as major early signs of infarction, including ischemic changes in more than one third of the area supplied by the middle cerebral artery.

The ATLANTIS study was initially designed to test the efficacy and safety of IV rt-PA in acute ischemic stroke when administered 0 to 6 hours after symptom onset; it was later restarted (and renamed the ATLANTIS Part B trial) to study the effects at 0 to 5 hours after concerns emerged for the 5- to 6-hour group. Results of the NINDS trial further reshaped the ATLANTIS Part B trial in 1996 to study only the 3- to 5-hour window.

The ATLANTIS Part B trial found no benefit for rt-PA over placebo in either the target population (TP; those without protocol violations) or the intention to treat (ITT) group.¹ The ITT group in this trial included 66 protocol violators who were treated within 3 hours, beyond 5 hours, or never given a study drug (TP, n5547; ITT, n5613). The risk of symptomatic ICH did not appear significantly higher compared to the NINDS trial, but the beneficial effects of rt-PA seen in the NINDS trial were not apparent.¹ Although groups were well matched demographically, 80% of patients in the target population were enrolled between 4 and 5 hours of symptom onset, rendering this study underpowered to evaluate the safety and efficacy for patients enrolled between 3 and 4 hours of symptom onset.¹

ECASS I randomized 620 patients with moderate or severe neurologic deficit and without major signs of infarction on initial CT. A statistically significant benefit was not found in the ITT analysis; however, the TP analysis demonstrated a significant advantage for the treatment group (ITT analysis median scores: 3 for the rt-PA group, 3 for the placebo group; TP analysis median scores: 2 for the rt-PA group, 3 for the placebo group).⁶ In both analyses, the overall rate of ICH, including fatal, nonfatal, and asymptomatic ICH, was significantly increased in the rt-PA group (ITT: 42.8% vs 36.8%, P ,.001; TP: 43.7% vs 36.7%, P ,.001).⁶

The most common protocol violation was inclusion of patients whose baseline CT showed hypodensity (ie, early infarct signs) that involved more than one third of the area supplied by the middle cerebral artery (58% of protocol violators). Of the ineligible patients, 61% were assigned randomly to the rt-PA group, an imbalance that the researchers admit they cannot explain. Those with large baseline hypodensities who received rt-PA had an extremely high rate of ICH, confirming the danger of thrombolytics in patients with extended early infarct signs. The authors concluded that rt-PA is effective in improving some functional measures in a defined subgroup, but it cannot be recommended in an unselected population because of the unacceptable increase in hemorrhagic complications and death.⁶

The ECASS I 3-hour cohort was published in 1998 as a secondary analysis of ECASS I data by time stratification. The majority of participants were seen in the 3- to 6-hour window, reflecting the greatest barrier to effective stroke therapy under current FDA indications⁷ (0-3 hours, n587; 3-6 hours, n5528). This study showed no significant differences in death or dependency for the rt-PA group over placebo in the 0- to 3-hour or 3- to 6-hour window, nor did it show any significant differences in functional outcome or hemorrhage between the two time-to-treatment subgroups. Interpretation of these results must consider the small patient numbers in the 0- to 3-hour window, as well as the greater number of protocol violators in this window (11% in 0-3 hours vs 8% in 3-6 hours).⁸

ECASS II used a lower dosage of rt-PA than ECASS I, to match NINDS criteria, and investigators received better CT training in comparison to ECASS I, in an attempt to reduce the number of protocol violators. Although the trial failed to show a statistically significant benefit using originally proposed definitions for favorable outcome, a post hoc analysis using alternative definitions showed patients acheived statistically significant increase in functional independence in the rt-PA group (54.3% vs 46%, P5.024).⁹ The authors concluded that despite the increased risk of ICH, thrombolysis with rt-PA in selected patients may lead to a clinically relevant improvement.⁹

The data were also analyzed by time stratification, with 635 patients (326 in the rt-PA group) in the 3- to 6-hour treatment window and 158 patients (81 in the rt-PA group) in the 0- to 3-hour window. Like ECASS I, the ECASS II time-stratified report did not show significant differences in functional outcome between the two time-to-treatment subgroups, again possibly reflecting the small sample size in the 0- to 3-hour group.⁹

Results

Using ITT data and original definitions proposed for favorable outcome, ATLANTIS Part B, ECASS I, and ECASS II failed to demonstrate significant benefit for rt-PA over placebo in the 3- to 6-hour window. ITT data from ECASS II did show a significant advantage for the rt-PA group when using an alternative dichotomization for the mRS. In addition, using the same alternate dichotomization for combined ITT data from both ECASS trials revealed similar treatment effects whether rt-PA was given within or beyond 3 hours of symptom onset (see "Delving further into the findings").¹⁰

Delving further into the findings

In addition to time of administration, other factors may be involved in functional outcome for patients given rt-PA, including the imaging modality used to assess the status of brain tissue, concomitant use of antithrombotics, stroke subtype, and dosage of rt-PA.¹
Brain tissue status

Recent data suggest that newer MRI techniques such as diffusion-weighted MRI (DWI) and perfusion-weighted MRI (PWI) are better than CT for identifying subgroups likely to respond to treatment beyond 3 hours.^2-4 The advantage of these two modalities over CT is that they have potential to differentiate salvageable ischemic brain tissue from irreversibly injured tissue, and the ability to predict both clinical outcome and final infarct volume.² DWI and PWI can be performed in approximately the same amount of time as CT and are becoming increasingly available. Although concerns have arisen that newer MRI modalities may miss acute intracranial hemorrhage, studies have shown that they can reliably identify hemorrhage.⁵ DWI and PWI appear extremely promising for uncovering potential benefits of thrombolysis, thereby helping to justify rt-PA administration after the 3-hour window in patients who have a high likelihood of favorable clinical response. Additional research is needed to establish utility and clarify cost-effectiveness.²
Concomitant use of antithrombotics

The MAST-I trial tested the interaction between thrombolytic therapy (streptokinase) and aspirin given simultaneously. Results revealed a significant increase in deaths, which was not offset by a reduction in morbidity or mortality at follow-up.¹ The MAST-I trial provides the only reliable evidence for concomitant use of antithrombotics, but reasonably reliable data based on nonrandomized comparisons are available for ECASS I and the ATLANTIS Part B trial. Results of these two trials showed an increased case fatality rate, supporting the evidence found in the MAST-I trial.¹ At this point, however, the data are insufficient regarding concomitant antithrombotic use.
Other variables

Unfortunately, the lack of direct comparisons between ATLANTIS, ECASS I, and ECASS II prohibits reliable conclusions regarding the effect of stroke subtype. Additional data are also needed on which dose of rt-PA has the least hazard and most benefit.¹
Further well-controlled, double-blind, randomized trials are needed to identify and filter out these confounding variables, as well as to establish the advantages of newer MRI techniques. The results of such trials should give us superior ability in choosing subgroups for delayed thrombolytic administration and potentially expand the current 3-hour treatment window. In the meantime, patients at risk for stroke should be instructed to recognize and respond to early stroke symptoms, and hospitals must streamline protocols and pathways for stroke treatment.⁶
1. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford, England: Update Software.
2. Albers GW. Advances in intravenous thrombolytic therapy for treatment of acute stroke. Neurology. 2001;57(5 suppl 2):977-981.
3. Thijs VN, Adami A, Neumann-Haefelin T, et al. Relationship between severity of MR perfusion deficit and DWI lesion evolution. Neurology. 2001;57:1205-1211.
4. Lee LJ, Kidwell CS, Alger J, et al. Impact on stroke subtype diagnosis of early diffusion-weighted magnetic resonance imaging and magnetic resonance angiography. Stroke. 2000;31:1081-1089.
5. Fisher M, Schaebitz W. An overview of acute stroke therapy: past, present, and future. Arch Intern Med. 2000;160:3196-3206.
6. Benavente O, Hart RG. Stroke: Part II. Management of acute ischemic stroke. Am Fam Physician. 1999;59:2828-2834.

Clinical bottom line

The case provides a typical scenario of delayed patient arrival in which thrombolytics would have been withheld. The current restrictive time window eliminates many potential recipients of rt-PA and is a significant barrier to effective stroke therapy.^1,4,7,11Although rt-PA appears to be beneficial in selected subgroups beyond 3 hours, its use in this patient, whose symptoms appeared outside the 3-hour window, is inappropriate under current FDA indications.

REFERENCES

1. Clark WM, Wissman S, Albers GW, et al. Recombinant tissue-type plasminogen activator (Alteplase) for ischemic stroke 3 to 5 hours after symptom onset. The ATLANTIS Study: A randomized controlled trial. Alteplase Thrombolysis for Acute Noninterventional Therapy in Ischemic stroke. JAMA. 1999;282:2019-2026.

2. Ringleb PA, Schellinger PD, Schranz C, Hacke W. Thrombolytic therapy within 3 to 6 hours after onset of ischemic stroke: useful or harmful? Stroke. 2002;33:1437-1441.

3. Wardlaw JM, Warlow CP, Counsell C. Systematic review of evidence on thrombolytic therapy for acute ischaemic stroke. Lancet. 1997;350:607-614.

4. Fisher M, Schaebitz W. An overview of acute stroke therapy: past, present, and future. Arch Intern Med. 2000;160:3196-3206.

5. Tissue plasminogen activator for acute ischemic stroke. The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. N Engl J Med. 1995;333:1581-1587.

6. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS [ECASS I]). JAMA. 1995;274:1017-1025.

7. Schneider AT, Pancioli AM, Khoury JC, et al. Trends in community knowledge of the warning signs and risk factors for stroke. JAMA. 2003;289:343-346.

8. Steiner T, Bluhmki E, Kaste M, et al. The ECASS 3-hour cohort. Secondary analysis of ECASS data by time stratification. ECASS Study Group. European Cooperative Acute Stroke Study. Cerebrovasc Dis. July-August 1998;8:198-203.

9. Hacke W, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Second European-Australasian Acute Stroke Study Investigators. Lancet. 1998;352:1245-1251.

10. Wardlaw JM, del Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. (Cochrane Review). In: The Cochrane Library, Issue 3, 2003. Oxford, England: Update Software.

11. Albers GW. Advances in intravenous thrombolytic therapy for treatment of acute stroke. Neurology. 2001;57(5 suppl 2):977-981.