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Frequently Asked Questions

Can the “window” for alteplase administration in ischemic stroke be extended to 4.5 hours?

Stroke is a leading cause of death worldwide. In the United States, approximately 600,000 new strokes occur each year, with a mortality rate of 50 per 100,000.1 The majority of strokes—about 87%—are ischemic, and the remainder are hemorrhagic (either intracerebral or subarachnoid). Although treatment options for hemorrhagic stroke are limited, specific recommendations for treatment of ischemic stroke are available. The goal for treatment of ischemic stroke is to restore cerebral perfusion, limiting damage to the brain and minimizing long-term disability.2 The most recent guidelines from the American College of Chest Physicians (ACCP) recommend the use of alteplase given within 3 hours of the onset of symptoms of ischemic stroke (rated as a strong recommendation with high-quality evidence). The dose of alteplase is 0.9 mg/kg (maximum of 90 mg), with 10% of the dose given as a bolus and the remainder infused over 60 minutes. This recommendation is based on the results of clinical trials that found significant reductions in death or dependency with the use of a thrombolytic within the 3-hour time period. Although improvement in outcomes is still seen with later administration of alteplase, there is some decline in the beneficial effects along with an increase in the risk of intracranial hemorrhage. Currently, the ACCP does not suggest the use of alteplase beyond 3 hours to 4.5 hours of symptom onset. This is rated as a slightly weaker recommendation, although it is based on high-quality evidence. Alteplase is not recommended for use in the treatment of stroke more than 4.5 hours after onset, with this recommendation rated at the highest grade.

Administering treatment within the 3-hour time period from symptom onset of stroke may be difficult. Treatment can be delayed by a number of factors, including failure to recognize stroke symptoms, transport time to the hospital, and time for diagnostic testing and drug preparation. Several recent studies have been conducted to assess the effectiveness of alteplase beyond 3 hours of symptom onset, but at less than 4.5 hours. The results of these trials can potentially lengthen the acceptable time of administration for alteplase following an ischemic stroke.

Studies evaluating alteplase at 3 hours or longer—SITS-ISTR and ECASS III

Wahlgren and colleagues published the results of the SITS-ISTR study (Safe Implementation of Treatment in Stroke-International Stroke Treatment Registry), an observational study evaluating the effects of alteplase given within 3 to 4.5 hours of symptom onset, in comparison with outcomes following administration of alteplase within 3 hours.3 SITS is a collaborative effort of over 700 clinical sites located worldwide that documents accepted treatments of stroke, using an interactive database. Included in the SITS-ISTR study was a subgroup of patients also treated with alteplase at European healthcare institutions and documented in SITS-MOST (SITS-Monitoring Study) registry. All patients received alteplase 0.9 mg/kg (up to 90 mg) infused over 1 hour (with 10% of the dose given as a bolus). Outcomes assessed included the rate of symptomatic intracerebral hemorrhage, functional independence (based on a modified Rankin scale) at 3 months, and mortality at 7 days and 3 months.

Data were available for 664 patients given alteplase between 3 and 4.5 hours of symptom onset and for 11,865 patients given the thrombolytic within 3 hours.3 The median time to treatment from stroke onset was 195 minutes for the 3- to 4.5-hour group and 140 minutes for the 3-hour group (difference=55 minutes; p<0.0001). The rate of symptomatic intracerebral hemorrhage was 2.2% with 3 to 4.5 hour alteplase compared with 1.6% with 3-hour alteplase for an odds ratio (OR) of 1.32 (95% confidence interval [CI] 1 to 1.75; p=0.052), based on the SITS-MOST criteria for intracerebral hemorrhage. Comparable between group differences (non-significant) were also found when other criteria for intracerebral hemorrhage were used (ECASS II [European-Australasian Acute Stroke Study] and NINDS [National Institute of Neurological Disorders and Stroke]). Mortality rates were comparable between the 2 treatment groups: 12.7% and 7.5% for 3-month and 7-day mortality with 3- to 4.5-hour alteplase and 12.2% and 6.5% for the 3 hour alteplase, respectively (p=0.72 and p=0.31). At 3 months, functional independence (modified Rankin score ≤ 2) was seen in 58.0% of patients in the 3- to 4.5-hour alteplase group and in 56.3% of patients in the 3-hour group (p=0.18). Although the authors concluded that alteplase was effective and safe when given beyond the 3-hour time period, it is important to note that the majority of the patients in the 3- to 4.5-hour alteplase group (nearly 60%) received the thrombolytic between 181 and 200 minutes, or only 20 minutes into the 3- to 4.5-hour time period. Outcomes were not stratified by any time intervals within the 3- to 4.5-hour time period.

The second trial, ECASS III, was conducted by Hacke and colleagues to compare alteplase given within 3 hours to alteplase given between 3 and 4.5 hours after onset of symptoms of acute stroke.4 Two earlier trials (ECASS and ECASS II) evaluated outcomes when alteplase was given within 6 hours of symptom onset.5,6 While neither of these earlier trials found a significant difference in primary outcomes with alteplase compared to placebo, the authors concluded that there was a trend towards a clinical benefit with alteplase for some functional outcomes.

In ECASS III, patients presenting within 3 to 4.5 hours of stroke onset were randomly assigned to treatment with either alteplase (0.9 mg/kg [up to 90 mg] infused over 1 hour, with 10% of the dose given as a bolus) or placebo.4 Heparin was permitted for prophylaxis of deep vein thrombosis, but no other anticoagulants, antiplatelets, or volume expanders were allowed during the first 24 hours of treatment. The primary outcome was disability at 3 months, categorized as either a favorable outcome (modified Rankin score 0 or 1) or an unfavorable outcome (modified Rankin score 2 to 6). Secondary outcomes included a global outcome measure (a combination of the modified Rankin score [score 0 or 1], Barthel index [score ≥ 95], NIHSS [National Institutes of Health Stroke Scale] score [0 or 1], and Glasgow Outcome scale [score 1]) and individual scores on functional measurement scales at 3 months. Rates of overall mortality, intracranial hemorrhage, or symptomatic edema were also assessed.

A total of 821 patients were enrolled in the trial and randomized to treatment.4 Approximately 10% of all patients were treated within 3 and 3.5 hours of symptom onset; 46.8% were treated within 3.5 to 4.0 hours; 39.2% were treated within 4 to 4.5 hours; the exact time of treatment was not available for the remainder of patients. In the alteplase group, a favorable outcome was achieved in 52.4% of patients, compared to 45.2% in the placebo group (OR 1.34 [95% CI 1.02 to 1.76]; p=0.04), based on an intention-to-treat analysis. Significance was also seen in favor of alteplase for the secondary global outcome measure, with a calculated OR of 1.28 (95% CI 1.00 to 1.65; p=0.02). For individual measures of functional outcome, 52.4% of patients given alteplase achieved a modified Rankin score of 0 or 1 and 50% achieved an NIHSS score of 0 or 1, compared with 45.2% and 43.2% of placebo patients (p=0.04 for both comparisons). For the 2 remaining outcome measures—the Barthel index and the Glasgow Outcome scale, no difference was seen between alteplase and placebo for percentage of patients achieving a favorable outcome (63.4% vs. 58.6% [p=0.16] and 51.0% vs. 45.4% [p=0.11] for alteplase and placebo, respectively). Rates of mortality were similar between the 2 treatment groups (7.7% and 8.4% [p=0.68] for alteplase and placebo), as were rates of symptomatic edema (9% and 7.2% [p=0.89]). However, intracerebral hemorrhage was more frequent with alteplase than with placebo—27.0% versus 17.6% (OR 1.73 [95% CI 1.24 to 2.42]; p=0.001). Symptomatic intracerebral hemorrhage was also higher with alteplase, regardless of the criteria used (ECASS III [2.4%], ECASS II [5.3%], SITS-MOST [1.9%], or NINDS [7.9%]; corresponding rates with placebo were 0.2%, 2.2%, 0.2%, and 3.5% (all between group comparisons significant).

Summary

Two recently published trials on the use of alteplase did find a significant beneficial effect of treatment when the thrombolytic was given beyond 3 hours of symptom onset. In SITS-ISTR, alteplase given at 3 to 4.5 hours after onset resulted in outcomes similar to those seen with early treatment (3 hours or less). However, in this study, the majority of patients in the 3- to 4.5-hour group received alteplase by 200 minutes after onset, only 20 minutes later than the 3-hour group. Also this study used an observational design and relied on data from an international registry of patients treated for ischemic stroke. ECASS III was a randomized trial comparing alteplase to placebo, both given 3 to 4.5 hours after stroke symptom onset. Alteplase was seen to be more effective than placebo; however, the risk of intracerebral hemorrhage was higher. The authors noted that the effect size seen with alteplase was clinically relevant—with a number needed to treat of 14, for 1 patient to have a favorable outcome with alteplase. However, the authors also stressed the importance of early treatment for ischemic stroke, initiating treatment at the shortest possible time from symptom onset.

Conclusion

Based on the results of 2 published trials, some patients may benefit from treatment with alteplase given past the current 3-hour time limit from symptom onset. However, the risk for intracerebral hemorrhage must be considered, and treatment should not be delayed for patients who do present within 3 hours of symptoms. It remains unclear if there is a difference in outcomes for patients treated early in the 3- to 4.5-hour extension versus those treated later (eg, 3 to 4 hours vs. > 4 up to 4.5 hours).

References

  1. Rosamond W, Flegal K, Furie K, et al. Heart disease and stroke statistics 2008 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation. 2008;117(4):e25-e126.
  2. Albers G, Amarenco P, Easton J, Sacco R, Teal P. Antithrombotic and thrombolytic therapy for ischemic stroke: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest. 2008;133(6 suppl):630S-669S.
  3. Wahlgren N, Ahmed N, Dávalos A, et al. Thrombolysis with alteplase 3-4.5 h after acute ischaemic stroke (SITS-ISTR): an observational study. Lancet. 2008;372(9646):1303-1309.
  4. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008;359(13):1317-1329.
  5. Hacke W, Kaste M, Fieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA. 1995;274(13):1017-1025.
  6. Hacke H, Kaste M, Fieschi C, et al. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352(9136):1245-1251.