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(Stroke. 2001;32:2709.)
© 2001 American Heart Association, Inc.
Controversies in Stroke |
Further Randomized Controlled Trials of tPA Within 3 Hours Are Required—NOT!
From the School of Medicine, University of California–San Diego.
Correspondence to Dr Patrick D. Lyden, UCSD School of Medicine, OPC Third Floor, Suite 3, 200 West Arbor Dr, San Diego, CA 92103-8466. E-mail plyden{at}ucsd.edu
Key Words: randomized controlled trials • stroke, acute • stroke, ischemic • thrombolysis • tissue plasminogen activator
Intravenous thrombolysis is beneficial for patients with acute ischemic stroke: in 5 separate trials, treated patients improved more than placebo patients. The first 2 trials, the NINDS trials, were published in 1995 and led directly to the licensing of recombinant tissue plasminogen activator (rtPA) for acute ischemic stroke. In these trials, patients were treated within 90 or 180 minutes of stroke onset with 0.9 mg/kg rtPA after a careful selection procedure. Treated patients enjoyed a near-total resolution of deficit more often (30% to 50% relative benefit) compared with placebo. Symptomatic hemorrhage occurred in 6.4% of treated patients. It is not widely appreciated that in addition to the treated patients who totally cleared their symptoms, an additional 20% to 30% enjoyed a partial improvement.1 A similar trial utilized intravenous ancrod, a defibrinogenating agent that causes modest thrombolysis, hypofibrinogenemia, and mild anticoagulation.2 Benefits and risks were similar to those with rtPA. In the PROACT II study, patients thrombolysed within 6 hours of symptom onset did well, with an acceptable hemorrhage rate.3 Finally, a large European trial of rtPA showed a clear benefit for rtPA, using the analysis method devised for the NINDS trials.4
The limitations on this therapy—the only proven stroke treatment—are legendary: patients must be treated promptly after stroke onset, must have no contraindications to thrombolysis, and must be treated by a team skilled in preventing potential complications. Much has been made of these limitations, to the point of considerable nihilism among neurologists. Yet, results similar to the NINDS data are obtained in communities with active stroke teams dedicated to proper use of intravenous thrombolysis. With only one exception, community experience with acute stroke therapy mirrors the NINDS trial results. Considerable prior experience is essential for appropriate case selection, but tutorials and basic texts are available.5
A red herring occasionally thrown at thrombolysis is the issue of vascular imaging: thrombolytic therapy might be given needlessly to some patients unless an image of the occluded artery is obtained. Reassurance may be found by considering that very few patients were treated "needlessly" in prior trials. For example, in the NINDS placebo group, only 2.6% of patients exhibited normal stroke scale scores 24 hours after stroke.6 This 2.6% included patients with transient ischemic attack and perhaps other nonstroke etiologies; it seems unlikely that vascular imaging prior to thrombolytic stroke therapy would add any benefit. Further, vascular imaging requires precious time: at least 60 minutes to mobilize and obtain the first images, even in the most dedicated centers.7 Further, it is apparently not harmful to administer tPA to patients in whom no blockage can be documented on angiogram: patients with lacunar syndromes responded to thrombolysis as well as or better than other subgroups.8 On the other hand, one important advantage of angiography is that intra-arterial therapy could be delivered directly into the clot. Recently, a large trial of intra-arterial prourokinase showed significant benefit with reasonable risk, even if treatment was delayed up to 6 hours following strok onset.3
Thrombolytic stroke therapy offers a real opportunity to eliminate stroke-related disability in some patients. Although the original trials met with appropriate skepticism, the results of these and subsequent stroke thrombolysis trials have been digested, criticized, confirmed, supplemented with additional data, and diffused widely. The therapy can be given to only a minority of patients, primarily those who present early enough, and only a minority enjoy a full response. So now, several questions must be answered: How can we increase the success rate? Will neuroprotectants add benefit or reduce risk when combined with thrombolytic therapy? Is the 3-hour time limit absolute, or is there some way to find patients in whom therapy could be given later? Most importantly, what can be done to educate more patients and potential stroke-witnesses about the signs of stroke and the need for immediate medical attention? Perhaps we will find a way to treat patients later than 3 hours, and further studies are needed to push the outer limit of the time window, but within the 3-hour window, no further trials are needed; the drug works. The dictum primum no nocere still applies: we must do no harm, either by actively committing an act or by withholding a proven therapy through inaction.
Footnotes
The opinions expressed in this editorial are not necessarily those of the editors or of the American Stroke Association.
References
1.
NINDS rt-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke. Stroke. 1997; 28: 2119–2125.
2.
Sherman DG, Atkinson RP, Chippendale T, Levin KA, Ng P, Futrell N, Hsu C, Levy DE, STAT Writers Group. Intravenous ancrod for treatment for acute ischemic stroke. JAMA. 2000; 283: 2395–2403.
3.
Furlan A, Higashida RT, Wechsler L, Gent M, Rowley HA, Kase C, Pessin M, Ahuja AT, Callahan F, Silver F, Clark WM, Rivera F, for the PROACT II Investigators. Intra-arterial prourokinase for acute ischemic stroke. JAMA. 1999; 282: 2003–2008.
4.
Hacke W, Bluhmki E, Steiner T, Tatlisumak T, Mahagne M-H, Sacchetti ML, Meier D. Dichotomized efficacy end points and global end-point analysis applied to the ECASS intention-to-treat data set. Stroke. 1998; 29: 2073–2075.
5. Lyden PD. Thrombolytic Therapy for Stroke. Totowa, NJ: Humana Press; 2001.
6. Lyden P, Lu M, Kwiatkowski T, Frankel M, Levine S, Broderick J, Brott T, and the NINDS rt-PA Stroke Study Group. Thrombolysis in patients with transient neurological deficits. Neurology. In press.
7.
del Zoppo G, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M, and the PROACT Investigators. PROACT: A phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. Stroke. 1998; 29: 4–11.
8. NINDS rt-PA Stroke Study Group. Generalized Efficacy of t-PA for Acute Stroke. Stroke. 1997; 28: 2119–2125.
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