Correspondence
Tissue Plasminogen Activator for Acute Ischemic Stroke
N Engl J Med 1996; 334:1405-1406May 23, 1996
- Article
To the Editor:
In “Tissue Plasminogen Activator [t-PA] for Acute Ischemic Stroke” (Dec. 14 issue),1 it is reported that treatment with t-PA increases a patient's chance of recovering from an ischemic stroke without any, or only minimal, disability or neurologic deficit. Despite this optimistic conclusion, several methodologic issues and the demonstrated risks of treatment with t-PA suggest a more cautious interpretation. Although the study was randomized, there were important base-line differences that favored the t-PA–treated patients. Overall, more patients in the t-PA–treated group than in the placebo group had been receiving aspirin before the event (odds ratio, 1.697; 95 percent confidence interval, 1.199 to 2.404; P = 0.002). This difference may have been more important than suggested by post hoc analysis, since some of the patients may have actually had a transient ischemic attack — for which aspirin is known to be beneficial — rather than a completed stroke. The importance of this possible pretreatment advantage may have been enhanced by the protocol, which precluded the use of aspirin or other antithrombotic therapy during the early phase of treatment. By contrast, the aspirin-like actions of t-PA would have been helpful to such patients.2
Another pretreatment advantage in the t-PA group was the presence of significantly more patients with small-vessel occlusions. As shown in the study, such patients are destined to have a better outcome irrespective of treatment, and, according to the study, the outcome is further improved by t-PA therapy.
Perhaps most discouraging was the finding, also evident in an earlier investigation of t-PA in stroke,3 that patients with early indications suggesting a devastating stroke are the ones at the greatest risk of having an untoward reaction to the drug. Indeed, it is somewhat puzzling that despite the increased number of deaths due to parenchymal hemorrhage among the t-PA–treated patients, this difference was not evident in the overall outcome, but emerged in another study.3 This study and the previous investigation3 suggest that t-PA therapy would benefit only a small subgroup of patients with stroke yet would expose a larger population to a potentially dire complication. Even when t-PA was administered within the context of a carefully controlled study, departure from the strict protocol resulted in a 50 percent increase in the mortality rate.3 It is not likely that the strict guidelines necessary to produce a small benefit in a limited number of patients who have had a stroke could realistically be adhered to in general practice.
3 ReferencesHoward S. Friedman, M.D.
Long Island College Hospital, Brooklyn, NY 112011
The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group
Full Text | Web of Science | Medline2
Kamat SG ,Michelson AD ,Benoit SE , et al. Fibrinolysis inhibits shear stress-induced platelet aggregation. Circulation 1995;92:1399-1407
Web of Science | Medline3
Hacke W ,Kaste M ,Fieschi C , et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995;274:1017-1025
CrossRef | Web of Science | Medline
To the Editor:
The National Institute of Neurological Disorders and Stroke (NINDS) rt-PA Stroke Study Group's positive findings in a trial of the thrombolytic agent t-PA for acute ischemic symptoms is a landmark study. Improved outcome in the treated group is clear. However, the paper does not provide the data necessary to guide the treatment of individual patients. Dissolution of clot in intracranial vessels is an obvious therapeutic goal in stroke. Intraarterial thrombolysis has been performed with dramatic angiographic and clinical success in certain instances.1 However, multiple (11) trials of intravenous thrombolysis have been plagued by the risk of fatal hemorrhage,2 which is most likely compounded by the relatively weak ability of intravenous agents to dissolve emboli and the difficulty of selecting appropriate patients on the basis of clinical criteria and computed tomography alone.
In the NINDS study, half the patients were treated within 90 minutes of the onset of symptoms, but the rate of fatal hemorrhage was increased ninefold by t-PA; rapid neurologic improvement, expected after recanalization, was rare; and there were no data regarding the incidence of recanalization. There are also major qualifications associated with the reported benefit. Some of the improved outcome with t-PA is related to the unequal randomization of patients with various types of stroke: as compared with patients assigned to placebo, 21 more patients with less severe, small-vessel disease and 18 fewer patients with more severe, large-vessel disease were assigned to t-PA. This by itself would improve outcome and reduce death in the treated group. Some of the overall benefit was due to better outcome in treating small-vessel occlusive disease, the natural history of which is the recovery of relatively good function. In their haste to treat all patients with ischemic deficits, physicians should be wary of causing fatal hemorrhage in patients who otherwise will have rapidly resolving deficits or tiny lacunes in the white matter. Patients with large-vessel occlusion are at highest risk for horribly disabling stroke if left untreated. In this group the risk of thrombolysis-induced fatal hemorrhage can be more easily accepted if there is a significant probability of improvement with t-PA. Did t-PA treatment in the NINDS study cause a statistically significant improvement in outcome in patients at risk for large-vessel strokes? Was treatment accompanied by an increase in death due to cerebral hemorrhage or cerebral edema? Treatment with t-PA is probably not indicated for every patient with an hour-long ischemic deficit. Before this therapy is introduced into general use, better criteria are needed to help select patients in whom the benefits outweigh the risks.
2 ReferencesWalter J. Koroshetz, M.D.
Massachusetts General Hospital, Boston, MA 02114for the Massachusetts General Hospital Stroke Service
1
Hacke W ,Zeumer H ,Ferbert A ,Bruckmann H ,del Zoppo GJ . Intra-arterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke 1988;19:1216-1222
CrossRef | Web of Science | Medline2
Wardlaw J, Yamaguchi T, del Zoppo G, Hacke W. Thrombolysis in acute ischaemic stroke. In: Warlow C, Van Gijn J, Sandercock P, eds. Stroke module, Cochrane database of systematic reviews. London: British Medical Journal Publishing, 1995.
To the Editor:
I would like to point out a discrepancy between the NINDS study of t-PA and Dr. del Zoppo's editorial (Dec. 14 issue)1 on this study. Dr. del Zoppo states, “patients with symptoms of cerebral ischemia . . . were randomly assigned to receive intravenous tissue plasminogen activator (t-PA) or placebo if they arrived at the hospital within three hours of the onset of symptoms.” In the study itself, the three-hour time limit actually pertains to the duration between the onset of symptoms of stroke and the time when treatment with t-PA or placebo was begun.
The discrepancy is important because, as del Zoppo points out, after arrival at the hospital the patients need to undergo a neurologic evaluation and computed tomography of the head and to provide informed consent before they undergo randomization and receive treatment.
1 ReferencesNauman Qureshi, M.D.
1005 W. Market St., Athens, AL 356111
del Zoppo GJ . Acute stroke -- on the threshold of a therapy? N Engl J Med 1995;333:1632-1633
Full Text | Web of Science | Medline
Author/Editor Response
The authors reply:
To the Editor: Dr. Friedman asks whether the beneficial effect we reported for t-PA in the treatment of acute stroke was due to the unequal distribution between the t-PA and placebo groups of patients who had been taking aspirin before their stroke. As we stated, the positive effect of t-PA on all outcome measures at three months was seen consistently in all subgroups categorized according to age, stroke subtype, severity of the stroke, and use of aspirin before the stroke. The imbalance in the randomization of patients taking aspirin before their stroke had little effect on the outcome of our trial because t-PA also increased favorable outcomes in those not taking aspirin.
Dr. Friedman and Dr. Koroshetz have questions regarding the risk and benefit of t-PA in various subgroups of patients with acute stroke. Both observed that there were more small-vessel occlusive strokes in the t-PA–treated group. It is true that patients assigned to the small-vessel occlusive category at base line were more likely to have a favorable outcome when treated with t-PA. But examination of Table 5 in our report shows that for each stroke subtype t-PA–treated patients had a favorable outcome more frequently than did patients who received placebo. Although stroke subtype helps predict outcome at three months, it does not help predict whether t-PA will be beneficial, since patients with all types of strokes have better outcomes when treated with t-PA.
The benefits of t-PA come at the expense of additional deaths due to intracerebral hemorrhage, but there are correspondingly fewer deaths due to other causes. Fewer t-PA–treated patients than placebo-treated patients had died at three months (17 percent vs. 21 percent).
Dr. Koroshetz is concerned that haste in treatment will expose patients to an unnecessary risk of intracerebral hemorrhage. On the contrary, we think that early treatment within three hours of the onset of stroke is required to obtain the full benefit of t-PA. Delaying treatment will not help select patients who will benefit from t-PA and may expose patients to a greater risk of hemorrhage, with less benefit in return.
This trial provides a basis for developing an acute care response to stroke. Further research may lower risks and increase benefits. In the meantime, we urge the development of the teams needed to treat stroke as the true emergency that it is.
John R. Marler, M.D.
National Institutes of Health, Bethesda, MD 20892for the NINDS-PA Stroke Study Group
Author/Editor Response
Dr. Qureshi raises an important point about the interval from the onset of stroke to the initiation of treatment with t-PA as opposed to the interval from stroke onset to arrival at the hospital in patients with acute ischemic stroke. Time to treatment was a relevant issue in the design of the NINDS rt-PA Stroke Study, as indicated by the time limitations of 90 and 180 minutes. But the difference in patient outcomes associated with those times was apparently not critical. Although unproved, the longer time before treatment in the European Cooperative Acute Stroke Study may have been partly responsible for the difference in the outcomes reported for that study.1 The point to be taken from both studies is that treatment requires the ready availability of high-quality brain-imaging techniques and a well-prepared medical team, which at this time are primarily available only at larger medical centers. The interval from stroke onset to arrival in the hospital is thus very important.
Furthermore, treatment without adherence to the strict clinical requirements outlined by these and other studies poses an unacceptable risk. In other words, initiating treatment without first performing the proper imaging studies is dangerous. Also, since the clinical impression of the time at which symptoms began may be quite subjective,2 proper techniques are needed to assess the severity and duration of the ischemic injury, both of which vary among patients.3 At this stage in the development of plasminogen activators for use in acute ischemic stroke, it is the delay in bringing the patient to medical attention (e.g., hospital) that must be addressed.
3 ReferencesGregory J. del Zoppo, M.D.
Scripps Research Institute, La Jolla, CA 920371
Hacke W ,Kaste M ,Fieschi C , et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke. JAMA 1995;274:1017-1025
CrossRef | Web of Science | Medline2
del Zoppo GJ ,Ferbert A ,Otis S , et al. Local intra-arterial fibrinolytic therapy in acute carotid territory stroke: a pilot study. Stroke 1988;19:307-313
CrossRef | Web of Science | Medline3
Baron JC ,von Kummer R ,del Zoppo GJ . Treatment of acute ischemic stroke: challenging the concept of a rigid and universal time window. Stroke 1995;26:2219-2221
CrossRef | Web of Science | Medline
- Citing Articles (3)
Citing Articles
1
H. J. Kim, H. K. Lee, H. Song, M. S. Ju, K. R. Dong, W. K. Chung, M. S. Cho, J. H. Cho. (2011) Reduction in radiation dose with reconstruction technique in the brain perfusion CT. Radiation Effects and Defects in Solids 166:12, 918-926
CrossRef2
Joanna M Wardlaw, Veronica Murray, Eivind Berge, Gregory J del Zoppo, Joanna M Wardlaw. 2009. Thrombolysis for acute ischaemic stroke. .
CrossRef3
Joanna M Wardlaw, Gregory J del Zoppo, Takenori Yamaguchi, Eivind Berge, Joanna M Wardlaw. 2003. Thrombolysis for acute ischaemic stroke. .
CrossRef
