Published online before print August 3, 2006, doi: 10.1161/01.STR.0000237210.15986.d6
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
(Stroke. 2006;37:2436.)
© 2006 American Heart Association, Inc.
Controversies in Stroke |
Intra-Arterial Thrombolysis Is the Treatment of Choice for Basilar Thrombosis
Pro
From the Departments of Neurology, University of Erlangen (P.D.S.) and University of Heidelberg (W.H.), Germany.
Correspondence to Peter D. Schellinger, MD, PhD, Neurologische Klinik, Universitätsklinikum Erlangen, Schwabachanlage 6, D-91054 Erlangen, Germany. E-mail Peter.Schellinger{at}neuro.imed.uni-erlangen.de
Key Words: thrombolysis
Parachutes to prevent death and disability from gravitational challenge.
The basis for parachute use is purely observational,
Apparent efficacy could be explained by a healthy cohort effect,
Individuals who insist that all interventions need to be validated by a RCT need to come down to earth with a bump.1
Basilar artery thrombosis (BAT) is a rare but most severe subtype of ischemic stroke often presenting with progressive or hyperacute brain stem symptoms, tetraplegia and loss of consciousness ranging from somnolence to frank coma. It is associated with a mortality between 50% and 90% in patients treated conventionally (antiplatelets or heparin) or not at all.2,3 If survived, the consequence frequently is a locked-in syndrome, the most gruelsome outcome thinkable. Different patterns include caudal vertebrobasilar, mid-basilar and top-of-the-basilar thrombosis, the former mostly being of atherothrombotic and the latter of embolic origin.4 Multiple case series mostly addressing intra-arterial (IA) and less frequently intravenous5 thrombolytic therapy for BAT have been published in the last 20 years, the first report by Zeumer et al dating back to 1982.6,7 Most studies suffered from small numbers: <10 patients with only a few in the range of 40 to 50 patients.2,8,9 All had an open, retrospective or partly prospective design with differing treatment regimens, mostly IA thrombolytic drugs formally rendering level III evidence at best.
Whereas some studies only used presence or absence of recanalization induced by a thrombolytic as a surrogate outcome, in all but 1 series it was shown that overall survival and an independent outcome was associated with successful partial or complete recanalization of the occluded basilar artery (BAO).2,8,9 Recanalization rates ranged from 40% to 100%, on average &50% to 60% in line with the results from the Prolyse in Acute Cerebral Thromboembolism II (PROACT II) trial.10 Survival in patients without recanalization ranged from 0% to 20% as opposed to 40% to 80% in those with recanalization. A recent meta-analysis by Lindsberg analyzed systematically published case series of 
10 patients reporting the outcome of BAO after IA or IV thrombolysis within 12 hours.11 In 420 BAO patients treated with IV thrombolysis (n=76) and IA thrombolysis (n=344), death or dependency were equally common: 78% (59 of 76) and 76% (260 of 344), respectively (P=0.82). Recanalization was achieved more frequently with IA thrombolysis (225 of 344; 65%) than with IV thrombolysis (40 of 76; 53%; P=0.05), but survival rates after IV thrombolysis (38 of 76; 50%) and IA thrombolysis (154 of 344; 45%) were similar (P=0.48). A total of 24% of patients treated with IA thrombolysis and 22% treated with IV thrombolysis reached good outcomes (P=0.82). Without at least partial recanalization, the likelihood of a good outcome was close to zero (2% versus 38%).
An Australian group ventured to perform a randomized trial (Australasian Urokinase Stroke Study)12 after a pilot trial (Australasian Urokinase Stroke Trial [AUST]) published in 1997.13 The pilot study included 15 patients within 31 hours (mean 18 hours) in an uncontrolled observational design. Eleven of 15 patients recanalized, 10 of these survived (only 1/4 nonrecanalizers). The AUS study was designed as an open-label, multicenter, randomized controlled trial with a blinded end point assessment and launched in 1996.12 Inclusion criteria were an acute posterior circulation stroke syndrome <24 hours time from symptom onset, age 18 to 85, and no hemorrhage on CT. Patients underwent digital subtraction angiography and, if a lysable lesion was identified, were randomized to either heparin (unfractionated, partial thromboplastin time [PTT] 60 to 80 s, 5000 IU bolus) or heparin plus IA urokinase (increments of 100 000 IU up to a maximum of 1 000 000 IU) followed by warfarin (international normalized ratio, 1.5 to 2.5) for 6 months. Clinical outcomes (modified Rankin Scale, National Institutes of Health Stroke Scale, Barthel Index) were independently assessed by a nurse or neurologist blinded for treatment. The study was terminated because of low recruitment (20 patients screened, 16 randomized). There were only 4 deaths in each group, 7/8 in the placebo group were disabled or dead, only 4 in the treatment group (ie, all survivors had an independent outcome). The early termination is disappointing because the total sample size would have been 65 patients (absolute effect size of 35%, 2-sided 
, power 0.8) to answer this question once and for all with IA thrombolysis for vertebrobasilar stroke becoming a level A recommendation.
Taking into account recent recommendations14 a new randomized study could screen with CT angiography, randomize 2 (active IA):1 (placebo), and have a consistent protocol regarding the therapeutic strategies such as concomitant treatment with abciximab, use of devices and other interventions.
We believe such a study would be desirable but it will never happen. The condition itself is rare, and we doubt that logistical problems can be overcome, and investigators at the expert centers with the largest experience will hesitate to randomize their patients. On the other hand, do we really need a new trial? Recanalization and reperfusion whether in anterior or posterior territory stroke is the strongest predictor if not a conditio sine qua non for survival and independence. The currently available data albeit not level I evidence provide more than enough information in favor of IA thrombolysis (maybe also IV thrombolysis) for BAT. In fact, in our opinion it is not the worst level of evidence if one can show that a drug designed to lyse clots can do exactly that in a considerable percentage of patients experiencing stroke attributable to an occluded vessel, and that those patients, whose vessels are reperfused have a far better outcome. In addition, upcoming studies using devices and add-on medications as well as PTA and stenting (eg, the Interventional Management of Stroke studies) likely will strengthen our point.15
Therefore, although we advocate randomized studies to answer several questions in acute and secondary prophylactic treatment of stroke we find it ethically unacceptable to randomize a patient to placebo versus conventional treatment thereby precluding him the chance of &50% for surviving an otherwise almost always deadly stroke and a &35% chance for being an independent survivor. We doubt that critics of IA thrombolysis for BAT would consent to inclusion in such a placebo-controlled study for themselves or their next of kin, like we doubt they would enter the above-mentioned parachute trial. At a certain point, patients with an infrequent disease with such a grim prognosis should be treated despite lack of level I evidence data. "Stop trying to control everything and just let go. Let go!"16
Received May 16, 2006; accepted June 12, 2006.
References
1. Smith GCS, Pell JP. Parachute use to prevent death and major trauma related to gravitational challenge: systematic review of randomized controlled trials. BMJ. 2003; 327: 1459–1461.
2. Hacke W, Zeumer H, Ferbert A, Brückmann H, del Zoppo G. Intraarterial thrombolytic therapy improves outcome in patients with acute vertebrobasilar occlusive disease. Stroke. 1988; 19: 1216–1222.
3. Schonewille WJ, Algra A, Serena J, Molina CA, Kappelle LJ. Outcome in patients with basilar artery occlusion treated conventionally. J Neurol Neurosurg Psychiatry. 2005; 76: 1238–1241.
4. Brandt T, Steinke W, Thie A, Pessin MS, Caplan LR. Posterior cerebral artery territory infarcts: Clinical features, infarct topography, causes and outcome. Multicenter results and a review of the literature. Cerebrovasc Dis. 2000; 10: 170–182.[CrossRef][Medline] [Order article via Infotrieve]
5. Lindsberg PJ, Soinne L, Tatlisumak T, Roine RO, Kallela M, Happola O, Kaste M. Long-term outcome after intravenous thrombolysis of basilar artery occlusion. JAMA. 2004; 292: 1862–1866.
6. Zeumer H, Hacke W, Kolmann HL, Poeck K. [Local fibrinolysis in basilar artery thrombosis (author’s translation)]. Dtsch Med Wochenschr. 1982; 107: 728–731.[Medline] [Order article via Infotrieve]
7. 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]
8. Brandt T, von Kummer R, Muller Kuppers M, Hacke W. Thrombolytic therapy of acute basilar artery occlusion. Variables affecting recanalization and outcome. Stroke. 1996; 27: 875–881.
9. Arnold M, Nedeltchev K, Schroth G, Baumgartner RW, Remonda L, Loher TJ, Stepper F, Sturzenegger M, Schuknecht B, Mattle HP. Clinical and radiological predictors of recanalisation and outcome of 40 patients with acute basilar artery occlusion treated with intra-arterial thrombolysis. J Neurol Neurosurg Psychiatry. 2004; 75: 857–862.
10. 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.
11. Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: A systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke. 2006; 37: 922–928.
12. Macleod MR, Davis SM, Mitchell PJ, Gerraty RP, Fitt G, Hankey GJ, Stewart-Wynne EG, Rosen D, McNeil JJ, Bladin CF, Chambers BR, Herkes GK, Young D, Donnan GA. Results of a multicentre, randomised controlled trial of intra-arterial urokinase in the treatment of acute posterior circulation ischaemic stroke. Cerebrovasc Dis. 2005; 20: 12–17.[Medline] [Order article via Infotrieve]
13. Mitchell PJ, Gerraty RP, Donnan GA, Fitt G, Tress BM, Thomson KR. Thrombolysis in the vertebrobasilar circulation - the Australian Urokinase Stroke Trial (AUST) pilot study. Cerebrovasc Dis. 1997; 7: 94–99.
14. Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, Dillon W, Warach S, Broderick J, Tilley B, Sacks D. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003; 34: e109–137.[CrossRef][Medline] [Order article via Infotrieve]
15. Major ongoing stroke trials. Stroke. 2006; 37: e18–e26.
16. Tyler (Brad Pitt), from the Fox movie "Fight Club"; 1999.
Related Articles:
Stroke 2006 37: 2440.
Stroke 2006 37: 2438-2439.
This article has been cited by other articles:
 |
|
 |
|
  M. Kohrmann and P. D. Schellinger Acute Stroke Triage to Intravenous Thrombolysis and Other Therapies with Advanced CT or MR Imaging: Pro MR Imaging Radiology, June 1, 2009; 251(3): 627 - 633. [Full Text] [PDF]
|
|
|
|
 |
|
 P. M. Meyers, H. C. Schumacher, R. T. Higashida, S. L. Barnwell, M. A. Creager, R. Gupta, C. G. McDougall, D. K. Pandey, D. Sacks, and L. R. Wechsler Indications for the Performance of Intracranial Endovascular Neurointerventional Procedures: A Scientific Statement From the American Heart Association Council on Cardiovascular Radiology and Intervention, Stroke Council, Council on Cardiovascular Surgery and Anesthesia, Interdisciplinary Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research Circulation, April 28, 2009; 119(16): 2235 - 2249. [Full Text] [PDF]
|
|
|
|
 |
|
 S. Nagel, P. D. Schellinger, M. Hartmann, E. Juettler, H. B. Huttner, P. Ringleb, S. Schwab, and M. Kohrmann Therapy of Acute Basilar Artery Occlusion: Intraarterial Thrombolysis Alone vs Bridging Therapy Stroke, January 1, 2009; 40(1): 140 - 146. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
T. Pfefferkorn, T. E. Mayer, C. Opherk, N. Peters, A. Straube, H.-W. Pfister, M. Holtmannspotter, S. Muller-Schunk, M. Wiesmann, and M. Dichgans Staged Escalation Therapy in Acute Basilar Artery Occlusion: Intravenous Thrombolysis and On-Demand Consecutive Endovascular Mechanical Thrombectomy: Preliminary Experience in 16 Patients Stroke, May 1, 2008; 39(5): 1496 - 1500. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J. Pagola, M. Ribo, J. Alvarez-Sabin, M. Lange, M. Rubiera, and C. A. Molina Timing of Recanalization After Microbubble-Enhanced Intravenous Thrombolysis in Basilar Artery Occlusion Stroke, November 1, 2007; 38(11): 2931 - 2934. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Ciccone, L. Valvassori, R. Gasparotti, F. Scomazzoni, E. Ballabio, and R. Sterzi Debunking 7 Myths That Hamper the Realization of Randomized Controlled Trials on Intra-Arterial Thrombolysis for Acute Ischemic Stroke Stroke, July 1, 2007; 38(7): 2191 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Lindsberg and H. P. Mattle Response to Letter by Schulte-Altedorneburg et al Stroke, January 1, 2007; 38(1): 10 - 11. [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||