To the Editor:
The report of Chiu et al1 showed that a single university hospital and 2 community hospitals could achieve results comparable to those of the recent NINDS rt-PA Study. Thirty patients were treated from a possible 267 patients appearing in the 3 emergency rooms.
Thirty-seven percent of the remaining 237 patients were rejected because the time limit for treatment was exceeded. This group accounts for nearly 3 times the number of patients actually treated. No mention in the paper was made of how these people fared or whether there was any attempt at follow-up. An age- and sex-matched control for those who were selected for treatment ought to be buried in this group of nearly 90 patients; the only distinguishing variable would be the time of onset.
It would be of great interest to know whether this control group had a worse outcome than the people receiving therapy. The report’s authors already may have the data or could obtain it. For most neurologists in practice over 10 years, their first experience with thrombolytic therapy was being called to the ICU after intracerebral hemorrhage when the therapy had been used for myocardial infarction. They next read the 4 negative studies on thrombolytic therapy before the NINDS Study. Their subsequent experience is likely to have been intense pressure from the media and academic powers-that-be to ignore the first 4 studies and to apply the therapy, along with pressure from hospitals in competition with others to use the latest (if not the best). The therapy may work as advertised, but further confirmatory data would be welcome.
Such data may already exist; Chiu and colleagues may actually have the data but have not written it up. Even if the patients rejected for therapy were not followed up in their study, it would not be difficult to do such a study and publish the results, since tPA appears to be the standard of care at present. My experience is that for every patient reaching the emergency room within 3 hours of stroke onset while awake, there are 2 or 3 otherwise identical patients who present after the 3-hour limit. Withholding thrombolytic therapy poses no ethical problem, as it is more likely to hurt these patients than to help.
- Copyright © 1998 by American Heart Association
Chiu D, Krieger D, Villar-Cordova C, Kasner SE, Morgenstern L, Brattina PL, Yatsu FM, Grotta JC. Intravenous tissue plasminogen activator for acute ischemic stroke. Stroke.. 1998;29:18–22.
We agree with Dr Robinson that the study of thrombolytic therapy for stroke does not end here. Our paper represents the first postmarketing survey of intravenous tPA for stroke to be published. Another recent multicenter analysis by Tanne and colleaguesR1 showed a symptomatic intracerebral hemorrhage rate of 3% in the first 36 hours after drug infusion. As a matter of quality control, every institution using tPA should track its incidence of symptomatic intracerebral hemorrhage.
Dr Robinson makes the interesting proposal of drawing an age- and sex-matched control group from patients presenting after the 3-hour limit. Although this could be done, the results of such a comparison would be prone to bias and difficult to interpret, as is the case with any nonrandomized clinical trial. Stroke patients who present to the emergency room within 3 hours of onset of symptoms are not average stroke patients in at least one respect—they have disproportionately severe strokes. Patients with mild neurological deficits are more likely to delay seeking medical attention. Patients with massive strokes tend to show up early. A statistical adjustment could be made for initial NIH stroke scale, but a given NIH score at 1 hour may have a different prognostic significance from the same score at 24 hours.
Fortunately for those of us attempting to examine our performance in clinical practice, the main challenge to thrombolytic therapy is the issue of safety rather than efficacy, although of course it is axiomatic that treatment decisions be based on risk-benefit ratio. For most centers, it is probably sufficient to ascertain that the incidence of complications and protocol violations is acceptably low (not significantly greater than 6.4% for symptomatic intracerebral hemorrhage).
As for the 4 negative studies on thrombolytic therapy to which Dr Robinson refers, they teach an important lesson as well. Their results indicate that we should not be using intravenous streptokinase or high-dose tPA beyond 3 hours for stroke. Whether 0.9 mg/kg intravenous tPA or intra-arterial thrombolysis are efficacious up to 6 hours after onset are questions being actively investigated in randomized clinical trials.