Expanding Recombinant Tissue Plasminogen Activator Time Window Is Premature
To the Editor:
The American Heart Association/American Stroke Association has expanded the time window for recombinant tissue plasminogen activator from 3 hours to 4.5 hours after stroke onset for many patients.1 The evidence2–7⇓⇓⇓⇓⇓ does not support a Class I recommendation (which will impact clinical care, quality measures, and medicolegal decisions), and we urge the American Heart Association/American Stroke Association to reconsider.
The new recommendation is based on the European Cooperative Acute Stroke Study III (ECASS III), a high-quality trial in 821 patients.2 ECASS III found recombinant tissue plasminogen activator within 3 to 4.5 hours after stroke onset to reduce the risk of death or dependency at 90 days (47.6% versus 54.8%, P=0.04, number needed to treat 14) despite an increase in any intracranial hemorrhage (27% versus 17.6% using the National Institute of Neurological Diseases and Stroke definition, P=0.001, number needed to harm 10) and in symptomatic intracranial hemorrhage (7.9% versus 3.5%, P=0.006, number needed to harm 22). In isolation, the ECASS III trial supports the recommendation.
However, there are 4 other randomized, placebo-controlled trials to consider. The Alteplase ThromboLysis for Acute Noninterventional Therapy in Ischemic Stroke (ATLANTIS) trial, a high-quality placebo-controlled trial in 613 patients, found recombinant tissue plasminogen activator within 3 to 5 hours after stroke onset had no significant differences in death or dependency at 90 days (66.2% versus 68%), a nonsignificant increase in mortality (11% versus 6.9%, P=0.09), and a significant increase in symptomatic intracranial hemorrhage (7% versus 1.1%, P<0.001, number needed to harm 17).3 Three other randomized, placebo-controlled trials (A0276g, ECASS, ECASS II) evaluated recombinant tissue plasminogen activator within 3 to 6 hours.4–6⇓⇓ Increases in intracranial hemorrhage were fairly consistent, but decreases in death or dependency were inconsistent.
Although a single pooled analysis of results from previous trials was reported,1 inconsistencies in the populations, outcome definitions, and results do not support a single pooled analysis.
Additional support for the new recommendation used an observational study of patients treated 3 to 4.5 hours (n=664) compared with patients treated within 3 hours after symptom onset (n=11 865).7 The study was summarized as having “no differences” in symptomatic intracerebral hemorrhage and mortality. However, the data suggest worse outcomes in the 3- to 4.5-hour time window group for symptomatic intracerebral hemorrhage (2.2% versus 1.6%, P=0.052) and mortality (12.7% versus 12.2%, P=0.053). A distinction must be made between “no differences” and “no statistically significant differences.” A trend toward harm that approaches the traditional threshold for statistical significance does not establish safety or equivalence.
With clear harms consistent across trials and inconsistent evidence for benefit, a Class I recommendation is not warranted. Further research establishing benefit in another high-quality randomized, placebo-controlled trial should be completed before making recombinant tissue plasminogen activator 3 to 4.5 hours after stroke onset a standard of care.
B.S.A. is Editor-in-Chief and C.B.B. is Deputy Editor of DynaMed, an evidence-based clinical reference.
- ↵Del Zoppo GJ, Saver JL, Jauch EC, Adams HP Jr; on behalf of the American Heart Association Stroke Council. Expansion of the time window for treatment of acute ischemic stroke with intravenous tissue plasminogen activator. A science advisory from the American Heart Association/American Stroke Association. Stroke. 2009; 40: 2945–2948.
- ↵Hacke W, Kaste M, Bluhmki E, Brozman M, Dávalos A, Guidetti D, Larrue V, Lees KR, Medeghri Z, Machnig T, Schneider D, von Kummer R, Wahlgren N, Toni D; ECASS Investigators. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med. 2008; 359: 1317–1329.
- ↵Clark WM, Wissman S, Albers GW, Jhamandas JH, Madden KP, Hamilton S. 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.
- ↵Clark WM, Albers GW, Madden KP, Hamilton S; Thromblytic Therapy in Acute Ischemic Stroke Study Investigators. The rtPA (alteplase) 0- to 6-hour acute stroke trial, part A (A0276g): results of a double-blind, placebocontrolled, multicenter study. Stroke. 2000; 31: 811–816.
- ↵Hacke W, Kaste M, Fieschi C, Toni D, Lesaffre E, von Kummer R, Boysen G, Bluhmki E, Höxter G, Mahagne MH, Hennerichi M. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. The European Cooperative Acute Stroke Study (ECASS). JAMA. 1995; 274: 1017–1025.
- ↵Hacke W, Kaste M, Fieschi C, von Kummer R, Davalos A, Meier D, Larrue V, Bluhmki E, Davis S, Donnan G, Schneider D, Diez-Tejedor E, Trouillas P. Second European-Australasian Acute Stroke Study Investigators. Randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998; 352: 1245–1251.