Response to Letter by Nichols et al
Dr Nichols et al, who we thank for their comments, emphasized the advantages of the combined IV and intra-arterial (IA) approach as compared with the IA approach alone. Should, therefore, the combined approach be privileged? Because there is usually the tendency to make things more difficult than they are when talking about the endovascular treatment of acute stroke, we would like to make some statements to clarify our point of view.
First, no trial whatsoever showed the superiority of IA therapy over IV rtPA1; therefore, it seems natural to try to make a direct comparison between the two. Such a trial would consist of a randomization between the gold standard and a “new” approach that is thought to be superior (but obviously still to be proven).
Second, the need for this comes from the experience of many centers of interventional neuroradiology in the last 15 years or more, but it comes also from the relatively limited effectiveness of the IV therapy, especially in severe strokes.2
Third, the disadvantage of the IA therapy in terms of time spent to prepare it as compared to the IV one should be compensated by a greater efficacy of the former. Such hypothesis should be tested in a randomized controlled trial (RCT).
Fourth, the combined approach has its advantages and disadvantages: to start immediately with IV therapy while IA therapy is organized avoids time wastage on one hand but could delay IA therapy on the other. Moreover, the combined-therapy approach exposes all the patients to the angiographic risks, including those who do not need IA thrombolysis and the decision whether to administer IA rt-PA is based on arteriographic rather than clinical data.
Fifth, in the EMS pilot trial (35 patients),3 no difference in the outcome was noted. Moreover, the way of arterial infusion consisted of a dose of 20 mg maximum over 2 hours, with no mechanical (not even with the microguidewire) help: it was a different experience and a different approach.
Sixth, IMS4 and IMS II5 trials are both case series, not RCTs. In both studies the authors reached the same conclusion: a randomized trial of standard IV rt-PA as compared with a combined IV and IA approach is needed.
As explained in our article regarding the myths of arterial therapy,1 we have a leading role in an ongoing multicenter RCT, named Synthesis,6 comparing IA and IV thrombolysis for acute ischemic stroke. We are going to conclude the start up phase and 15 centers in Italy have applied for an expansion phase of the study (Synthesis Expansion), with financial support from AIFA, the Italian National Agency for Drugs.
Our idea is: let’s make a comparison between the gold standard, that is IV thrombolysis with rt-PA, and “best IA thrombolysis”, which might include drug but also mechanical devices.
Best IA approach might differ in different centers and even for different operators in the same center, but it is our opinion that there is a basic homogeneity in the way of thinking and behaving in the neuroendovascular world that will eventually make these differences much smoother.
Furthermore, we are not looking for the winning recipe: there are probably many ways to achieve a recanalization and a good outcome. The aim is not to find the right device or the good drug and dose. The aim is to assess whether IA approach, inclusive of different procedures that can be adopted for different subjects, is useful for patients experiencing an acute ischemic stroke.
We agree that a direct comparison of IV rt-PA alone and the combined approach is needed but, contrary to the Cincinnati group, we still think that a direct comparison of IV rt-PA alone and the IA approach alone is likewise needed. And that is what we are doing. A simple trial for a simple idea.
The authors of this letter are involved in an ongoing multicenter randomized, controlled trial, comparing intra-arterial and intravenous thrombolysis for acute ischemic stroke. A.C. is the principal investigator; L.V. and R.S. are members of the steering committee.
Ciccone A, Valvassori L, Gasparotti R, Scomazzoni F, Ballabio E, Sterzi R. Debunking 7 myths that hamper the realization of randomized controlled trials on intra-arterial thrombolysis for acute ischemic stroke. Stroke. 2007; 38: 2191–2195.
The NINDS t-PA Stroke Study Group. Generalized efficacy of t-PA for acute stroke: subgroup analysis of the NINDS t-PA Stroke Trial. Stroke. 1997; 28: 2119–2125.
Lewandowski CA, Frankel M, Tomsick TA, Broderick J, Frey J, Clark W, Starkman S, Grotta J, Spilker J, Khoury J, Brott T. Combined intravenous and intra-arterial r-tPA versus intra-arterial therapy of acute ischemic stroke: Emergency Management of Stroke (EMS) Bridging Trial. Stroke. 1999; 30: 2598–2605.
IMS Study Investigators. Combined intravenous and intra-arterial recanalization for acute ischemic stroke: the Interventional Management of Stroke Study. Stroke. 2004; 35: 904–911.
The IMS II Trial Investigators. The Interventional Management of Stroke (IMS) II Study. Stroke. 2007; 38: 2127–2135.
Major Ongoing Stroke Trials. Intra-Arterial Versus Intravenous Thrombolysis in Acute Ischemic Stroke (SYNTHESIS). Stroke. 2007; 38: e119–e120.