A Clinical Debate: Should t-PA be the First-Line Treatment for Acute Ischemic Stroke?


Synopsis: To identify stroke subtypes that achieve the greatest long-term benefit from thrombolytic therapy, physicians need to establish a patho-anatomical vascular diagnosis in their CT-negative acute stroke patients, using noninvasive means.

Sources: Caplan LP, et al. (Con) Grotta J. (Pro) N Engl J Med 1997;337:1309-1312.

Caplan et al characterize tissue plasminogen activator (t-PA) as a dangerous drug with limited relevance as therapy for ischemic stroke. Their point is that the only established beneficial effect of thrombolysis is the lysis of acute thromboemboli.1 The causes of ischemic stroke are heterogeneous: large artery atherosclerosis with superimposed thrombosis, occlusive disease of small arteries, arterial dissections, and embolic arterial occlusions. Not all embolic strokes are due to lysable blood clots. Other materials such as calcium particles, cholesterol crystals, and myxoma tumor emboli may compose

embolized material. Therefore, many patients with acute ischemic stroke who are eligible for intravenous (IV) t-PA do not have lysable thromboemboli. In these patients, thrombolytic therapy is dangerous as well as ineffective.

It is also necessary to distinguish between embolic occlusions of middle cerebral artery branches that respond to IV t-PA and occlusions of the internal carotid artery, main stem of the middle cerebral artery, and the basilar artery that respond better to intra-arterial therapy. To accomplish this, Caplan et al recommend the use of noninvasive vascular imaging techniques, such as extracranial and transcranial ultrasonography and magnetic resonance angiography. They conclude that both brain and vascular imaging should always precede thrombolysis to ensure specificity of diagnosis and allow selection of an appropriate route, IV or intra-arterial, for t-PA.

In rebuttal, Grotta points out that the NINDS trial2 found t-PA beneficial in patients with all subtypes of stroke and could not identify a group of patients who were non-responders. He concedes that t-PA is dangerous but only if given too late or to the wrong patient, namely one with evidence of a hemorrhagic stroke or of extensive ischemic changes on baseline CT. Such patients, as well as those with uncontrolled hypertension (BP = 185/110 mmHg or greater), should be excluded from thrombolytic therapy according to practice guidelines already published.3 Furthermore, the majority of hemorrhages that occurred in the NINDS trial were in patients with severe strokes who probably would have died or been left disabled without treatment.

Grotta concludes that t-PA is a highly effective treatment for ischemic stroke, but, even at his own institution in 1996, it was given to only "6-7% of all patients with stroke." Therefore, he exhorts neurologists, internists, and specialists in emergency medicine to develop protocols and clinical pathways and to put this therapy to the test of routine clinical use.


The evidence from the NINDS trial is that patients with acute ischemic stroke who survive t-PA therapy are less disabled at three months after treatment. The general public has absorbed this information, and most patients who arrive in the Emergency Department soon after stroke onset, like patients with acute myocardial infarction, expect to receive clot-dissolving treatment. In general, acute stroke patients and their families accept the trade-off of a 5-6% risk of cerebral hemorrhage to reap the long-term benefit of t-PA therapy. Furthermore, many stroke patients would prefer to die from their stroke or its treatment rather than to survive in a disabled state.4

Nevertheless, as urged by Caplan et al, physicians need, as often as possible, to establish a patho-anatomical vascular diagnosis in their CT-negative acute stroke patients, using noninvasive means. Such diagnostic specificity will permit the identification of stroke subtypes that achieve the greatest long-term benefit from thrombolytic therapy. Data from several thousand treated patients will be needed for a systematic review. Until such information is available, premature judgments should not lead physicians to withhold t-PA from an appropriate patient with an ischemic stroke. (Dr. Caronna is Vice-Chairman, Department of Neurology, Cornell University Medical Center, Professor of Clinical Neurology, New York Hospital.)


    1. Pessin MS, del Zoppo GJ, Furlan AJ. In: Moskowitz MA, Caplan LR eds. Cerebrovascular Diseases: Nineteenth Princeton Stroke Conference. Boston: Butterworth-Heinemann, 1995:409-418.

    2. The NINDS rt-PA Stroke Study Group. N Engl J Med 1995;333:1581-1587.

    3. Practice advisory: Thrombolytic therapy for acute ischemic stroke. Neurology 1996;47:835-839.

    4. Solomon NA, et al. Stroke 1994; 25:1721-1725.