Response to Letter by Ciccone et al
The authors Ciccone and Scomazzoni make a note on our systematic analysis of thrombolytic treatment of basilar artery occlusions.1 They raise the point that indirect comparison of case series does not provide new evidence of efficacy in an area that has not been studied with randomized controlled trials (RCT). Our main effort was to collect and compare therapy results of as coherently confirmed acute basilar artery occlusions (BAO) as possible in an established management routine, either with intra-arterial (IAT) or intravenous thrombolysis (IVT). A RCT is from the scientific point of view the highest standard to answer a specific treatment question, but a poor randomized trial does not give better results or gives perhaps worse advice than a careful analysis of the existing data and of carefully designed case registries. Our concern has been that in BAO a RCT is difficult to perform because of low numbers of patients per center that may result in selection bias and low recruitment.
Unlike Ciccone and Scomazzoni we would not discourage to continue to collect case series. Case series have, in addition to RCTs, given much useful information in the past. For instance, we know both from case series and RCTs the characteristics of patients who are likely to benefit from IVT or IAT or both, and this information on predictors of outcome helps for treatment decision in a given patient. BASICS is a registry for BAO where we would encourage to enter data on patients with BAO (www.brains.umcutrecht.nl). From IAT trials and series we know that stroke patients and their outcome are very heterogeneous. Outcome depends mainly on location of the occlusion in the cerebral vessel. Further predictors of outcome are NIHSS on admission, time to treatment, collaterals as seen on arteriography, age, recanalization grade, diabetes and post-thrombolytic hemorrhage. Such information should also be used for a stratified randomization, when a trial comparing IVT and IAT is designed. Not all patients are candidates for IVT, and not all patients are candidates for IAT, and of all the predictive factors we can influence only time to treatment, recanalization and to some extent hemorrhagic complications of thrombolysis.
In another point we also disagree with Ciccone and Scomazzoni. IAT cannot be called any longer a “virtuosistic play for few”. There is solid evidence from RCTs that IAT is a therapy and not a play. The evidence comes from PROACT I and II, which randomized patients with M1 and M2 MCA occlusions, and from AUST with vertebrobasilar occlusions. The evidence of efficacy is not as firm as for IVT; however, altogether 236 patients have been treated with IAT in RCTs (Table). The result is a significant treatment effect of IAT (P=0.018).
The current evidence is that IAT is a treatment option for many patients when the time for IVT has elapsed, and in most centers performing IAT, the indication for arteriography and IAT is based both on clinical findings and imaging with diffusion- and perfusion-weighted MR and MR angiography. IVT has yet to prove its efficacy beyond the 3 hours time window, whereas IAT has already done this in patients with confirmed MCA occlusions. We agree with Ciccone and Scomazzoni that comparisons of IVT and IAT are needed, especially in the time window for which health authorities have approved use of rt-PA and we congratulate them on their initiative with the SYNTHESIS trial. However, randomization of patients in future RCTs comparing IAT and IVT should adhere to defined standards and use stratification with functional MR or CT imaging to prevent heterogeneity and imbalance between the groups to be compared and exclude patients not suitable for endovascular treatment from the study.5 This would eliminate difficulties in obtaining clinically meaningful data even from relatively small RCTs, which presently prevent us from making firm management recommendations in BAO based on analysis of case series or registries.
Lindsberg PJ, Mattle HP. Therapy of basilar artery occlusion: a systematic analysis comparing intra-arterial and intravenous thrombolysis. Stroke. 2006; 37: 922–928.
del Zoppo GJ, Higashida RT, Furlan AJ, Pessin MS, Rowley HA, Gent M. PROACT: a phase II randomized trial of recombinant pro-urokinase by direct arterial delivery in acute middle cerebral artery stroke. PROACT Investigators. Prolyse in Acute Cerebral Thromboembolism. Stroke. 1998; 29: 4–11.
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.
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.
Higashida RT, Furlan AJ, Roberts H, Tomsick T, Connors B, Barr J, Dillon W, Warach S, Broderick J, Tilley B, Sacks D. Technology Assessment Committee of the Am Society of Interventional and Therapeutic Neuroradiology; Technology Assessment Committee of the Society of Interventional Radiology. Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke. Stroke. 2003; 34: e109–137.Epub 2003 Jul 17. Erratum in: Stroke. 2003;34:2774.