Correspondence

Thrombolysis 3 to 4.5 Hours after Acute Ischemic Stroke

N Engl J Med 2008; 359:2839-2841December 25, 2008

Article

To the Editor:

Since the 1995 publication of a study1 reporting the efficacy of intravenous thrombolysis with alteplase for limiting the devastating effects of acute ischemic stroke, we have learned repeatedly that successful thrombolysis is time-dependent. Despite initial skepticism regarding the benefit of such therapy, subsequent trials have replicated similar efficacy, effectiveness, and safety and have continued to emphasize that “time is brain.” In the European Cooperative Acute Stroke Study (ECASS) III trial (Sept. 25 issue),2 Hacke et al. discuss the benefit of intravenous thrombolysis with alteplase administered up to 4.5 hours after the onset of stroke symptoms. Although the findings of previous trials of extended-treatment windows were inconclusive,3 the success of ECASS III beyond 3 hours may reflect earlier treatment (an average of 30 minutes sooner) than the previous extended-window study, reaffirming the need for speed.

In addition, interval improvements in stroke care with the development of stroke systems and comprehensive attention to multiple care aspects beyond thrombolysis may also underlie the success shown in ECASS III. Yet, complacency about time must not prevail. Much work remains, including understanding pathophysiology that limits time, exploring physiology that may extend time, and developing approaches for late-presenting patients with stroke. It is clearly time to erase any vestige of nihilism from acute stroke treatment.

Michel T. Torbey, M.D., M.P.H.
Medical College of Wisconsin, Milwaukee, WI 53226
tfort@stroke.org

Edward Jauch, M.D.
Medical University of South Carolina, Charleston, SC 29425

David S. Liebeskind, M.D.
University of California at Los Angeles Medical Center, Los Angeles, CA 90095

for the Acute Stroke Advisory Board of the National Stroke Association

Dr. Jauch reports receiving consulting fees from Genentech.

No other potential conflict of interest relevant to this letter was reported.

3 References

1
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995;333:1581-1587
Full Text | Web of Science | Medline

2
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;359:1317-1329
Full Text | Web of Science | Medline

3
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. JAMA 1999;282:2019-2026
CrossRef | Web of Science | Medline

To the Editor:

Worldwide demographic changes mean that increasingly, elderly patients will make up the majority of those at risk for stroke. In our institution, 58% of people who are admitted with acute stroke are over the age of 80 years.1 A review of this subgroup showed that 50% of these patients would have been eligible for thrombolysis on the basis of neuroimaging alone. Yet the current evidence base would make it necessary to consider thrombolysis for such patients as an off-license indication.

Yet again, an important trial, ECASS III, has automatically excluded patients over the age of 80 years, which leaves clinicians with a dilemma. Such age cutoffs have been used in most studies in this field,2-4 with the exception of the National Institute of Neurological Disorders and Stroke trial,5 which included a small number of patients over the age of 80 years. We think that the practice of excluding patients from clinical trials on the basis of age alone limits the application of the trials' findings and should be reviewed.

Aine E. Fitzpatrick, M.R.C.P.I.
Imelda Noone, A.N.P.
Diarmuid D. O'Shea, M.D., F.R.C.P., F.R.C.P.I.
St. Vincent's University Hospital, Dublin D4, Ireland

5 References

1
Noone I, O'Shea D, Crowe M. Stroke in the very old. Ir Med J 2008;101:8-9
Medline

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). JAMA 1995;274:1017-1025
CrossRef | Web of Science | Medline

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). Lancet 1998;352:1245-1251
CrossRef | Web of Science | Medline

4
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. JAMA 1999;282:2019-2026
CrossRef | Web of Science | Medline

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

To the Editor:

In discussing the use of intravenous alteplase beyond 3 hours after the onset of symptoms, Hacke et al. do not estimate the number of additional patients who might benefit from such therapy. No data are provided on the median door-to-needle times, but if we assume that most U.S. centers require 60 minutes to deliver intravenous thrombolytic drugs, then data on stroke arrival times that are available from the American Heart Association's Get with the Guidelines–Stroke database can be used to generate an estimate.1 From 2003 through 2007, a total of 164,000 patients with ischemic stroke presented to more than 700 participating hospitals with documented times of stroke onset and hospital arrival. An average of 13% arrived between 2 and 3.5 hours after stroke onset (Table 1Table 1Percentage of Patients with a Specified Interval between the Onset of Symptoms of Ischemic Stroke and Arrival at a Hospital.). Assuming that 678,600 patients have an ischemic stroke per year,2 an additional 82,218 patients could be evaluated, of whom at least 26,465 (approximately 30%) could be treated.3 The 7% benefit of extending the treatment window to 4.5 hours that was observed in ECASS III translates to 1852 more patients with reversal of their stroke disability annually. Telemedicine and transport to stroke centers will probably be needed to broadly increase treatment rates.4

Lee H. Schwamm, M.D.
Massachusetts General Hospital, Boston, MA 02114
lschwamm@partners.org

Gregg C. Fonarow, M.D.
David Geffen School of Medicine at UCLA, Los Angeles, CA 90095

4 References

1
LaBresh KA, Reeves MJ, Frankel MR, Albright D, Schwamm LH. Hospital treatment of patients with ischemic stroke or transient ischemic attack with the “Get With The Guidelines” program. Arch Intern Med 2008;168:411-417
CrossRef | Web of Science | Medline

2
Heart disease and stroke statistics — 2008 update. Dallas: American Heart Association, 2008.

3
Barber PA, Zhang J, Demchuk A, Hill MD, Buchan AM. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology 2001;56:1015-1020
Web of Science | Medline

4
Schwamm LH, Pancioli A, Acker JE III, et al. Recommendations for the establishment of stroke systems of care: recommendations from the American Stroke Association's Task Force on the Development of Stroke Systems. Circulation 2005;111:1078-1091
CrossRef | Web of Science | Medline

To the Editor:

The recent finding by Hacke et al. that the treatment window for stroke with the use of intravenous alteplase can be extended from 3 to 4.5 hours is a small but important step. However, the results need to be viewed and tempered in the context of the overall stroke population. Most stroke patients present well beyond 6 hours, and many have an unknown time of onset.1 Moreover, many patients with acute stroke who present within 4.5 hours are excluded from thrombolysis because of the many (>15) exclusion criteria. These facts are further defined in the study itself, since it took investigators at 130 sites 3 years to enroll 821 patients, an average of 2.1 patients per year per site. In addition, the original protocol was extended by 0.5 hour to include more patients, since enrollment was not optimal. There is no question that properly selected patients with acute stroke should be treated with intravenous alteplase. However, the design of future drugs and trials, both preclinical and clinical, should focus on the treatment of stroke that will benefit the vast majority of patients rather than a small minority.

Daniel C. Morris, M.D.
Henry Ford Health Systems, Detroit, MI 48230
dmorris4@hfhs.org

1 References

1
California Acute Stroke Pilot Registry (CASPR) Investigators. Prioritizing interventions to improve rates of thrombolysis for ischemic stroke. Neurology 2005;64:654-659
CrossRef | Web of Science | Medline

Author/Editor Response

Torbey et al. rightfully conclude that the results of our study reflect the general improvement of stroke care in stroke centers. They suggest that the results may also convince skeptics about thrombolysis within 3 hours. We agree that there is no room for nihilism anymore and that these results may help to increase treatment within 3 hours and the number of hospitals with an active thrombolysis program.

Fitzpatrick et al. are concerned about the age limit of 80 years in our study. The cutoff reflects European labeling of alteplase for such treatment within 3 hours. Therefore, the age limit had to become part of the study design. In consequence, the treatment of patients over the age of 80 years in Europe will remain off-label, even under 3 hours.

Schwamm and Fonarow calculate the potential number of additional patients who could undergo treatment with a possible expansion of the approval for intravenous alteplase up to 4.5 hours after the onset of symptoms. We did not attempt to estimate such numbers in our article, but we tend to agree that a substantial number of additional patients could be treated. Numbers will differ from country to country and center to center, but the doubling of the number of treated patients is a possibility. They also discuss the door-to-needle time, which was longer than 1 hour on average in our study, a fact that we consider an area in which major improvement is still needed.

Morris discusses the high number of patients arriving after 6 hours and the various exclusion criteria that limit the number of patients eligible for intravenous alteplase. Thrombolysis is a treatment that has potential risks, and therefore exclusion criteria are important and must be respected. Further expansion of the time window may be possible and would require more sophisticated imaging technology, but even then, only a few additional patients would become eligible. Comprehensive stroke centers must continue to take every measure to increase the number of patients who arrive early enough to be treated.

Morris also comments on the slow recruitment in the first phase of our study. Basically, it is extremely difficult to randomly assign patients to study groups during a 1-hour treatment window. With a median door-to-needle time of more than 1 hour (including the obtaining of informed consent), the expansion of the time window by just 30 minutes made the difference in recruitment.

Werner Hacke, M.D., Ph.D.
Ruprecht Karls Universität, D-69120 Heidelberg, Germany
werner.hacke@med.uni-heidelberg.de

Markku Kaste, M.D., Ph.D.
University of Helsinki, SF-00029 Helsinki, Finland

Danilo Toni, M.D., Ph.D.
La Sapienza, I-00185 Rome, Italy

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