Published online before print April 8, 2004, doi: 10.1161/01.STR.0000126038.53283.d4
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2004;35:1139.)
© 2004 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Outcome of Acute Stroke Patients Without Visible Occlusion on Early Arteriography
Neurologische Universitätsklinik, Heidelberg, Germany
To treat, or not to treat: that is the question: Whether ’tis nobler in the mind to suffer The uncertainties rendered by open case series, Or to take arms against a sea of troubles, And by performing adequate trials end them?— —Modified from William Shakespeare’s Hamlet (III, i)
At present, only intravenous thrombolysis (IVT) with recombinant tissue plasminogen activator (rt-PA) administered within 3 hours after symptom onset is proven to be effective for the treatment of acute stroke. Based on level I evidence from the NINDS trial and several meta-analyses, rt-PA has been approved in many countries around the world, including the USA, Canada, Australia, and most of Europe. A recent meta-analysis (Marler et al, Lancet 2004, in press) also demonstrates a significant effect of rt-PA in the 3- to 4.5-hour window, albeit that has not changed approval regulations. National and international committees and guidelines name IVT with rt-PA within the 3-hour time window as the first-line treatment of choice. In specific, the European Stroke Initiative (EUSI) states "intravenous rt-PA (0.9 mg/kg, maximum 90 mg), with 10% of the dose given as a bolus followed by an infusion lasting 60 minutes, is the recommended treatment within 3 hours of onset of ischemic stroke (level I)" and "the benefit from the use of intravenous rt-PA for acute ischemic stroke beyond 3 hours after onset of the symptoms is smaller, but present up to 4.5 hours (level I)."1 The American Stroke Association (ASA) guidelines state: "intravenous rt-PA (0.9 mg/kg, maximum dose 90 mg) is strongly recommended for carefully selected patients who can be treated within 3 hours of onset of ischemic stroke (grade A)."2
Intraarterial thrombolysis (IAT) has been tested in multiple case series with multiple substances3 and only one randomized controlled trial positive for pro-urokinase within 3 to 6 hours (level I [ASA] to II [EUSI] because of relatively small sample size) has been published so far,4 but has not sufficed for FDA approval. The EUSI states: "intraarterial treatment of acute MCA [middle cerebral artery] occlusion in a 6-hour time window using pro-urokinase results in a significantly improved outcome (level II)" and "acute basilar occlusion may be treated with intraarterial therapy in selected centers in an institutional protocol as experimental therapy or within a multicenter clinical trial (level IV)."1 The ASA states: "IAT is an option for treatment of selected patients with major stroke of <6-hour duration due to large vessel occlusions of the middle cerebral artery (grade B)" and "importantly, the availability of IAT should generally not preclude the administration of intravenous rt-PA in otherwise eligible patients."2
It has been an endeavor of many groups to improve the selection of patients for IVT as well as IAT, and to define which patients to treat and which not to treat. Several case series, open trials, or trials with historical controls used MRI criteria, such as the PWI/DWI–mismatch, or arteriographic criteria for IAT, such as presence and site of a vessel occlusion.5,6 Larger phase II and III trials addressing these problems are under way (eg, DIAS/DEDAS, DEFUSE, EPITHET).7 In the current issue of Stroke, Arnold et al8 present a subgroup of their patients (N=28/283) who were arteriographically screened for IAT with urokinase (not pro-urokinase!) but not treated because of absence of a vessel occlusion. The median baseline NIHSS score was 7, time from symptom onset to arteriography ranged from 1 hour 55 minutes to 5 hours 15 minutes (mean: 3 hours 46 minutes). After 3 months, 21 patients (75%) were independent (modified Rankin Scale score [mRS] 
2). However, in 22 patients, infarcts were seen at follow-up imaging. Although no predictors of clinical outcome were identified, the authors concluded that patients with normal early arteriography usually will experience a favorable clinical outcome when not treated and discourage thrombolysis in these patients.
From a pathophysiological point of view, it makes sense to treat patients with thrombolytics who have proof of an obliterating thrombus, and to withhold a potentially threatening therapy in patients without a therapeutical substrate. There are only few data about the outcome of patients with patent vessels on early arteriography,6 and, to my knowledge, outcome data of the PROACT II patients screened with arteriography but not randomized (N=294 142 of these without or with incomplete vessel occlusion) have not been published. Therefore, the observations of Arnold et al are interesting, albeit not surprising. However, with the evidence at hand, the authors should test their hypothesis in a controlled, maybe even randomized, small trial (IAT versus saline in acute stroke patients 3 to 6 hours with thrombolysis in myocardial infarction [TIMI] 2 and 3 flow). Although they will unlikely detect a clinical difference because of small numbers, this would preclude withholding IVT from eligible patients and render a study with a higher evidence level. Granted, this limitation has been discussed.
Nevertheless, it is disturbing that 25% of patients each were either dependent/dead (median baseline NIHSSS of 9, outcome mRS 3 to 6) or had remaining nonincapacitating functional deficits (median baseline NIHSSS of 7, outcome mRS 2). Eight of 28 patients underwent arteriography within 3 hours (20 underwent arteriography within 4.5 hours), 1 had residual symptoms (mRS 2), and 3 were dependent or dead. When assuming a 30-minute delay caused by arteriography, 10 of 28 patients could have received IVT <3 hours and 24 of 28 patients within 4.5 hours, with the latter not approved but with sound level I evidence in favor of IVT with rt-PA. Mild or improving stroke symptoms are the reason for withholding IVT in one third of patients, and, again, one third of these have a poor outcome.9 Also, even lacunar infarcts without an arteriographic vessel occlusion may profit from IVT.10 Furthermore, microcirculatory defects can be overlooked on arteriography. Although recanalization most likely is an independent predictor of good outcome, tissue reperfusion may be even more important in congruence with MI in cardiology. Approved therapies based on level I evidence and recommended by most expert panels and stroke societies should not be discarded in favor of open noncontrolled studies.2
In conclusion:
By indirections find directions out. (Hamlet, II, i)
More matter with less art. (Hamlet, II, ii)
Or ...
In keeping with the times, not open case series but imaging-based studies with at least a control to obtain a higher level of evidence should be designed. Simple IVT with early reperfusion may be more helpful than invasive angiography without IAT.
 |
References |
|---|
 Top References |
|---|
- The European Stroke Initiative Executive Committee and the EUSI Writing Committee. European stroke initiative recommendations for stroke management—update 2003. Cerebrovasc Dis. 2003; 16: 311–337.[CrossRef][Medline] [Order article via Infotrieve]
- Adams HP Jr, Adams RJ, Brott T, del Zoppo GJ, Furlan A, Goldstein LB, Grubb RL, Higashida R, Kidwell C, Kwiatkowski TG, Marler JR, Hademenos GJ. Guidelines for the early management of patients with ischemic stroke: a scientific statement from the Stroke Council of the American Stroke Association. Stroke. 2003; 34: 1056–1083.
[Free Full Text] - Schellinger PD, Fiebach JB, Mohr A, Ringleb PA, Jansen O, Hacke W. Thrombolytic therapy for ischemic stroke-a review. Part II—intra-arterial thrombolysis, vertebrobasilar stroke, phase IV trials, and stroke imaging. Crit Care Med. 2001; 29: 1819–1825.[CrossRef][Medline] [Order article via Infotrieve]
- Furlan A, Higashida R, Wechsler L, Gent M, Rowley H, Kase C, Pessin M, Ahuja A, Callahan F, Clark WM, Silver F, Rivera F. Intra-arterial prourokinase for acute ischemic stroke. The proact II study: a randomized controlled trial. Prolyse in acute cerebral thromboembolism. JAMA. 1999; 282: 2003–2011.
[Abstract/Free Full Text] - Röther J, Schellinger PD, Gass A, Siebler M, Villringer A, Fiebach JB, Fiehler J, Jansen O, Kucinski T, Schoder V, Szabo K, Junge-Hülsing GJ, Hennerici M, Zeumer H, Sartor K, Weiller C, Hacke W. Effect of intravenous thrombolysis on MRI parameters and functional outcome in acute stroke <6h. Stroke. 2002; 33: 2438–2445.
[Abstract/Free Full Text] - Derex L, Tomsick TA, Brott TG, Lewandowski CA, Frankel MR, Clark W, Starkman S, Spilker J, Udsten GJ, Khoury J, Grotta JC, Broderick JP. Outcome of stroke patients without angiographically revealed arterial occlusion within four hours of symptom onset. AJNR Am J Neuroradiol. 2001; 22: 685–690.
[Abstract/Free Full Text] - Major ongoing stroke trials. Stroke. 2003; 34: e61–72.[Medline] [Order article via Infotrieve]
- The ATLANTIS, ECASS, and NINDS rt-PA Study Group Investigators. Association of outcome with early stroke treatment: pooled analysis of ATLANTIS, ECASS, and NINDS rt-PA stroke trials. Lancet. 2004; 363: 768–774.[CrossRef][Medline] [Order article via Infotrieve]
- Barber PA, Zhang J, Demchuk AM, Hill MD, Buchan AM. Why are stroke patients excluded from TPA therapy? An analysis of patient eligibility. Neurology. 2001; 56: 1015–1020.
[Abstract/Free Full Text] - Chalela JA, Ezzeddine M, Latour LL, Warach S. Reversal of perfusion and diffusion abnormalities after intravenous thrombolysis for a lacunar infarction. J Neuroimaging. 2003; 13: 152–154.[CrossRef][Medline] [Order article via Infotrieve]
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||