Response to Letter by Furlan
We read with great interest the comment by Dr Furlan regarding the controversy on whether it is ethical to randomize patients to placebo within the 3- to 6-hour time window.
When we were asked to be part in this controversy debate, we were assigned to present a clearcut “no” opinion.1 However, we do acknowledge the point raised by Davis and Donnan that probably another level of evidence is needed to support the worldwide acceptance of imaging-guided treatment in the extended time window.2 This is not because neurologists and interventionalists are not convinced that treatment works, but a lot of patients with stroke around the world are still treated by nonneurologists (ie, internal medicine and emergency physicians). Equipoise among stroke neurologists is one important point raised by Dr Furlan, but nevertheless, it is the equipoise among all stroke treating physicians that will decide if this treatment will reach a significant proportion of principally eligible patients. As we have learned over the past decade, for expample, (American) emergency physicians are notoriously tough to convince. Hence, clear evidence may be needed before such a new treatment regimen will be widely accepted and implemented. If we do not succeed in providing such evidence, probably more patients may be harmed by not being treated at all than patients would need to be assigned to placebo in such a trial. Thus, one could argue that few patients will have to suffer (receiving placebo) for the sake of thousands that could benefit once a carefully designed and well-performed international trial is performed. The last sentence puts us into the key point: In our opinion, as shown by the recently completed trials, pure feasibility is not in question. However, planning and performing the trial the way it needs to be done is the key point and this will be the responsibility of us as stroke experts. Careful design and, more importantly, diligent conduction of the trial are also key to justify randomizing patients and to honor those who may receive placebo.
It comes down to every stroke center potentially being a part of such a pivotal international effort. With the work that has been done on the treatment of patients in the extended time window, especially the progress that has been made in imaging-based patient selection, we have gained a clear vision of whom we want to treat and whom we better not.3 No question that the concept is not perfect yet but needs more research to be refined. However, as shown in several large observational studies, even this—call it “unpolished”—approach works within daily clinical practice.4,5 So are we willing to include exactly those patients we believe we should be treating into a placebo-controlled trial? If yes, there is no room for hesitation or uncertainty and, in the end, recruiting only patients into the trial that we in our heart do not want to treat.
Are we willing to include patients who are (1) young; (2) previously healthy individuals with (3) proximal vessel occlusion; (4) small baseline diffusion-weighted imaging lesion; (5) large perfusion-weighted imaging/diffusion-weighted imaging mismatch; and (6) without severe comorbidities? Or, as Grotta and Barreto said, are we willing to be included ourselves?6 Are we willing to have our family members included? If the answer to all those questions would be that those patients should be treated anyway and will not be randomized, then we end up with a study population of older patients only (ie, >70 years old); severe pre-existing illness; no visible vessel occlusion; no or insignificant mismatch; severe comorbidities; and patients who are not us or anyone we know.
If that is our trial, to solve this question, then good luck. This will do more harm than good and will certainly not answer the question accordingly. If we decide to perform a trial, we call for a joint, sincere international effort to solve this once and for all. In our opinion, such an international trial would be the only way to justify placebo patients at this point.
Kohrmann M, Schwab S. Is it ethical to have a placebo arm in reperfusion trials in the 3- to 6-hour time window? No: time frame or time gain? Stroke. 2009; 40: 1543–1544.
Donnan GA, Davis SM. The ethics of thrombolytic trials beyond 3 (or 4.5) hours: randomized controlled trials are required to change clinical practice. Stroke. 2009; 40: 1545.
Albers GW, Thijs VN, Wechsler L, Kemp S, Schlaug G, Skalabrin E, Bammer R, Kakuda W, Lansberg MG, Shuaib A, Coplin W, Hamilton S, Moseley M, Marks MP. Magnetic resonance imaging profiles predict clinical response to early reperfusion: the Diffusion and Perfusion Imaging Evaluation for Understanding Stroke Evolution (DEFUSE) study. Ann Neurol. 2006; 60: 508–517.
Schellinger PD, Thomalla G, Fiehler J, Kohrmann M, Molina CA, Neumann-Haefelin T, Ribo M, Singer OC, Zaro-Weber O, Sobesky J. MRI-based and CT-based thrombolytic therapy in acute stroke within and beyond established time windows: an analysis of 1210 patients. Stroke. 2007; 38: 2640–2645.
Grotta J, Barreto A. Is it ethical to have a placebo arm in reperfusion trials in the 3- to 6-hour time window? Yes. Stroke. 2009; 40: 1541–1542.