Response to Letters by Asimos and by Alper and Brown
We are grateful for the queries of Drs Asimos and Alper and Brown. Dr Asimos, in responding to the recent Science Advisory Statement regarding treatment with recombinant recombinant tissue plasminogen activator in a 3.0- to 4.5-hour window, based on the published European Cooperative Acute Stroke Study (ECASS) III study results,1,2⇓ makes the reasonable point that patients with blood glucose levels >400 mg/dL (22.2 mmol/L) should be excluded from treatment in this interval. We agree. As we stated in the Statement, patients with blood glucose levels of >400 mg/dL were excluded from treatment in ECASS III,2 and these patients were also excluded from treatment in the National Institute of Neurological Diseases and Stroke-sponsored study.3 As noted in the Statement, in addition, patients with a history of diabetes and a history of stroke were excluded from ECASS III and should also be excluded from treatment in a 3.0- to 4.5-hour interval.1,2⇓
Regarding the handling of patients presenting with blood glucose levels >400 mg/dL in the Guidelines for the management of patients with acute ischemic stroke, that document is in the process of revision, and the next statement will specifically address the issue of recombinant tissue plasminogen activator administration in this subgroup of patients based on Dr Asimos’ comments, current practice, and new published data.
Drs Alper and Brown also raise an issue that is of clinical relevance and offer an opportunity to correct a common misimpression regarding American Heart Association methodology in rating practice recommendations. For the Science Advisory Statement, the strength of the evidence supporting a recommendation is reflected in the Level of Evidence grade assigned to each recommendation, not the class grade assigned (see the classification table on the second page). The class grade reflects the magnitude of the treatment effect.
The Writing Committee recognized that the evidence for recombinant tissue plasminogen activator in the 3.0- to 4.5-hour window was not supported by 2 independently positive trials, but rather by retrospectively pooled subgroup data from several trials4 and an independent prospective positive trial.2 Accordingly, a Level of Evidence grade of B, rather than A, was assigned to the recommendation. We disagree with some aspects of Drs Alper and Brown’s review of the evidence, particularly their adducing data from 4.5- to 6.0-hour window patients when considering a treatment recommendation in the 3.0- to 4.5-hour interval. Nonetheless, we did recognize that the estimate of certainty regarding the evidence from the available trial data were less than absolute and rendered the Level of Evidence Grade B accordingly. As a result, the revised American Heart Association ischemic stroke guidelines assign a lower Level of Evidence grade (B) to intravenous recombinant tissue plasminogen activator in the 3.0- to 4.5-hour window than either the revised European (A) or Canadian (A) guidelines.5,6⇓
The Writing Committee did find assigning a class grade indicating the size of treatment effect challenging, wrestling with choosing between the class Grades I and IIa. The degree of treatment benefit in the 3.0- to 4.5-hour window, based on the point estimates, is less than in the <3.0-hour window. The published ECASS III trial results suggest that for every 100 patients treated between 3.0 and 4.5 hours, 16.3 patients are helped and 2.7 are harmed.7 Here the help-to-harm ratio is nearly 6.8 There is precedence for a Class I recommendation for the use of catheter delivery of certain plasminogen activators in a similar setting based on a similar help-to-harm.9 After much discussion, we assigned a Class I grade.
These issues about the new prospectively derived data indicate some of the reasons why more information about the data is needed.
G.J.d.Z. is employed at the University of Washington. J.L.S. is employed at the University of California at Los Angeles; has received research support from Concentric (modest); honoraria from Concentric Medical, Boehringer Ingelheim, and Ferrer (all modest); and has served as a consultant to CoAxia (modest), Talecris (modest), ev3 (modest), Ferrer (modest), Concentric Medical (modest), and Cygnis (modest). E.C.J. is employed at Medical University of South Carolina; has received research support from Novo Nordisk (modest); and has served as a consultant to Genentech (modest). H.P.A. is employed at the University of Iowa; and has received honoraria from Optum Health and National Stroke Association (both modest).
- ↵Del Zoppo GJ, Saver JL, Jauch EC, Adams HP. 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, Davalos 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.
- ↵Hacke W, Donnan G, Fieschi C, Kaste M, von Kummer R, Broderick JP, Brott T, Frankel M, Grotta JC, Haley EC Jr, Kwiatkowski T, Levine SR, Lewandowski C, Lu M, Lyden P, Marler JR, Patel S, Tilley BC, Albers G, Bluhmki E, Wilhelm M, Hamilton S; ATLANTIS Trials Investigators; ECASS Trials Investigators; NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768–774.
- ↵ESO Executive Committee, ESO Writing Committee. European Stroke Organization Guideline Update, January 2009. Available at: www.eso-stroke.org/pdf/ESO%20Guidelines_update_Jan_2009.pdf.
- ↵Lindsay P, Bayley M, Hellings C, Hill M, Woodbury E, Phillips S. Canadian best practice recommendations for stroke care (updated 2008) CMAJ. 2008; 179: S1–S25.
- ↵Saver JL, Gornbein J, Grotta J, Liebeskind D, Lutsep H, Schwamm L, Scott P, Starkman S. Number needed to treat to benefit and to harm for intravenous tissue plasminogen activator therapy in the 3- to 4.5-hour window: joint outcome table analysis of the ECASS 3 trial. Stroke. 2009; 40: 2422–2437.
- ↵Demaerschalk BM. Thrombolytic therapy for acute ischemic stroke: the likelihood of being helped versus harmed. Stroke. 2007; 38: 2215–2216.
- ↵Adams HP Jr, del Zoppo G, Alberts MJ, Bhatt DL, Brass L, Furlan A, Grubb RL, Higashida RT, Jauch EC, Kidwell C, Lyden PD, Morgenstern LB, Qureshi AI, Rosenwasser RH, Scott PA, Wijdicks EF; American Heart Association; American Stroke Association Stroke Council; Clinical Cardiology Council; Cardiovascular Radiology and Intervention Council; Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups. Guidelines for the early management of adults with ischemic stroke: a guideline from the American Heart Association/American Stroke Association Stroke Council, Clinical Cardiology Council, Cardiovascular Radiology and Intervention Council, and the Atherosclerotic Peripheral Vascular Disease and Quality of Care Outcomes in Research Interdisciplinary Working Groups: the American Academy of Neurology affirms the value of this guideline as an educational tool for neurologists. Stroke. 2007; 38: 1655–1711.