(Circulation. 1995;92:2794-2795.)
© 1995 American Heart Association, Inc.
Articles |
More on Thrombolysis and Hemorrhagic Stroke
From the Medizinische Klinik II, Städtische Kliniken Kassel, Germany.
Correspondence to Prof Dr Karl-Ludwig Neuhaus, Städtische Kliniken Kassel, Medizinische Klinik II, Mönchebergstr 41-43, D-34125 Kassel, Germany.
Key Words: thrombolysis • stroke • bleeding • Editorials
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Introduction |
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Bleeding complications, including catastrophic intracranial hemorrhage, have always been the inevitable downside of thrombolytic therapy. When the concept of early reperfusion was introduced into the therapy of acute myocardial infarction,1 2 previous intravenous thrombolytic regimens were drastically shortened to a 1-hour high-dose infusion, not only to increase efficacy but also to reduce bleeding risks.3 4 From subsequent large-scale trials,5 6 however, a persistent significant hazard of intracranial hemorrhage was observed. With the advent of the more fibrin-specific thrombolytic tissue-type plasminogen activator (TPA) along with an improved efficacy, a lower bleeding risk was anticipated. Again, the incidence of hemorrhagic strokes turned out to be even higher with the new drug than with streptokinase.7 8 9 We still do not know whether TPA is just not sufficiently fibrin specific or whether fibrin specificity per se does not help to reduce the bleeding risk. The answer will be given in the near future by new, completely fibrin-specific thrombolytics such as staphylokinase10 or TNK, a mutant of wild-type TPA,11 which currently are being investigated in phase II clinical trials.
With currently available drugs, thrombolytic therapy saves about 30 lives per 1000 patients with acute myocardial infarction presenting with ST-segment elevation or bundle-branch block. About 3 of those 1000 patients, however, will die, and another 1 or 2 will suffer a disabling hemorrhagic stroke from thrombolysis.12
In an outstanding effort, the GUSTO investigators have provided more detailed information on incidence, category, and outcome of stroke after thrombolysis. They systematically evaluated all the strokes in a 40 000–patient trial on thrombolysis in acute myocardial infarction13 and achieved an unprecedented (at least in large trials) 93% rate of anatomic documentation, mostly by computed tomography: almost 600 patients with a diagnosis of stroke. Together with an adequate analysis of functional outcomes, these data provide a rational basis for a more adequate risk assessment with regard to hemorrhagic and ischemic strokes, death rates, and disability after therapy with the most widely used thrombolytic drugs, streptokinase and accelerated TPA.
It is of interest to note that the incidence of intracranial bleeding is higher than in previous megatrials, probably because of the special emphasis put on detection and reporting of these events. Although a disabling stroke will be recognized in virtually all instances, the true incidence of fatal hemorrhagic strokes may be even higher, especially during the early hours of the clinical course, because in critically ill patients the contribution of a cerebral event to disastrous deterioration may be missed. Another open question is the potential value of neurosurgical intervention for intracranial bleeding in the particular context of thrombolysis and acute myocardial infarction.
The most intriguing piece of information in this article, however, is the results of a quality-of-life substudy, which highlight an unresolved problem in the risk-benefit assessment of thrombolytic treatment, the relative weight of an intracranial hemorrhage. For most clinicians, a hemorrhagic stroke is rated at least as catastrophic as death.14 Is this rating appropriate, and if so, do the patients agree with this rating?
There are several reasons that may help to explain why we perceive a hemorrhagic stroke as a most catastrophic event. If the complication is fatal, we know almost surely that this particular patient died of the treatment. If the patient survives with a severe deficit, we face an individual who not only is physically disabled but in many cases has irreversibly lost his or her personality and psychophysical integrity, which puts a significant emotional stress and an almost inevitable feeling of guilt on the treating physician.
Furthermore, for simple numerical reasons, an excess event rate of much less than 1% achieves an unquestionable statistical significance just because it is so close to zero. In any megatrial, an absolute difference of 50 hemorrhagic strokes, eg, 0.3% versus 0.8%, is a highly significant hazard; in the same trial, an excess of 50 deaths, eg, 8.3% versus 8.8%, would be regarded as almost negligible in terms of statistical significance. Consequently, the statistical weight of a given number of excess adverse events is very different on the risk and the benefit sides, although the patient probably would not care too much about the statistical weight of his or her individual fate. To overcome this obvious asymmetry, the GUSTO investigators calculated the so-called net clinical benefit, which is the difference between the sums of deaths and disabling strokes for one treatment versus another.5 In this equation, a disabling stroke, hemorrhagic or ischemic, is still rated as being equivalent to death. This concept has been generally accepted by the clinical community, but what about the patients' "rating"?
The GUSTO investigators addressed this most important dimension,13 which had been completely neglected in the discussion of thrombolysis and stroke. In the quality-of-life substudy of GUSTO-1, they asked the patients how much of a hypothetical 10-year survival they would give up to live the remaining years in excellent health. At variance from the physicians' perception, even the severely disabled apparently would not prefer to have died instead of suffering a disabling stroke. They wanted to give up just 2 more years of their hypothetical 10-year survival than those with no major residual deficit. Although such an answer to a hypothetical question does not cover the whole complex issue and the number of disabled patients interviewed was low, it clearly indicates that at least these patients did not rate their strokes as equivalent to or even worse than death.
These findings strongly suggest a major discrepancy between our rating (and the emphasis put on a minor, albeit significant, risk in previous discussions) and the patients' appreciation of these risk-to-benefit relations. The latter, however, should guide our reasoning and decision making in the first place. A less emotional rating that is more oriented to the patients' wishes would greatly affect the risk-benefit considerations in high-risk patients such as the elderly and those with hypertension, who at present, despite a most probable net clinical benefit, are often denied thrombolytic therapy.
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Footnotes |
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The opinions expressed in this editorial are not necessarily those of the editors or of the American Heart Association, Inc.
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References |
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