Response to Letters by Furlan, and Kohrmann and Schwab
Drs Furlan, Kohrmann, and Schwab make compelling arguments. However, we still maintain that placebo-controlled trials of stroke therapy beyond 3 hours are ethical, and in fact necessary.
First, our editorial was written before the results of ECASS 3. We now believe there is sufficient evidence from that study and the pooled analysis of all IV tPA data that further clinical trials of treatment in the 3- to 4.5-hour time window must allow IV tPA for all eligible patients. Of course, we are in the uncomfortable situation where, at least in the United States, data and evidence move faster than guidelines and regulatory approval. Individual physicians and patients may not treat with IV tPA in the absence of such gudielines/approval, but we do not believe that clinical trials should be organized that preclude offering such treatment. However, for patients who do not qualify for IV tPA, or cannot be treated within 4.5 hours of symptom onset, placebo arms can still be used.
Second, Dr Furlan argues that such trials are not feasible, but the clear answer obtained from placebo-controlled trials beyond 3 hours such as ECASS 3 and PROACT (both positive), and the numerous neuroprotection trials and DIAS 2 (all neutral or negative) demonstrate that clear-cut answers can be obtained from such studies using existing clinical trial designs. It is worth noting that the 2 positive studies did not use any fancy selection criteria or trial design features advocated by Dr Furlan to “minimize” the placebo group. There may be a difference in this regard between clinical trials evaluating simple widely applicable treatments such as adjuncts to IV tPA like intravenously administered antithrombotic agents, or neuroprotective therapies which can more easily enroll larger numbers of patients at multiple centers. Endovascular therapy trials, because of the inherent limitations of endovascular therapy as described by Dr Furlan, may require the more complex design features he advocates, but a placebo arm is still necessary until more data are available that demonstrate that the benefits of this treatment are worth the risks and costs, and for which patients. Furthermore, as the authors of DIAS-2 point out, the criteria to optimize the selection and treatment outcomes of >3-hour patients remain elusive.1 Here, we agree with him that some heretofore unused trial design to conserve resources should be considered. Perhaps the target group of patients with mismatch (or however we finally determine is a valid way to identify the continued existence of penumbra by imaging or biomarkers) treated early may not require a placebo arm, whereas less ideal candidates may. Eventually, perhaps the use of data from large patient registries such as VISTA may provide sufficiently precise models to predict outcome that we might be able to use these data to “minimize” the placebo group.
Third, in response to Dr Furlan’s “equipoise” argument, we think that what is considered ethical, or offered to our patients in or out of clinical trials, should be based on data and not a vote. Basing such decisions on opinion invites bias and uninformed decisions due to conflict of interest or lack of information in the group of individuals who are asked to vote. Interventionalists clearly have a conflict of interest in this question that certainly could influence whether >70% consider a nontreatment arm ethical. Even vascular neurologists would vote differently depending on whether they practice in an environment where interventional or investigational therapies are readily available. On the other hand, asking patients or other groups not familiar with existing data (and lack thereof) invites opinion based on fantasy rather than facts. An analogy would be asking me if I am in favor of reincarnation—certainly I would answer “yes,” but I certainly am not recommending any adjustment of my behavior in this life based on that vote.
Finally, the question we were asked is whether placebo arms are still ethical in clinical trials. Perhaps equipoise is different in academic centers whose mission is to answer questions and move the field forward, as opposed to clinical practice where, in the absence of data, we are forced to make a decision in each patient based on a synthesis of what we think we know. We feel that equipoise still exists in academic centers conducting clinical trials such as our own which has been routinely offering endovascular rescue therapy since 1996. There are 19 institutions that are actively recruiting into the placebo-controlled MR Rescue trial and the study recently passed its halfway point of recruitment. We applaud Drs Donnan and Davis for their efforts in the EXTEND trial (phase 3, placebo-controlled thrombolysis trial). The goal of clinical research is to generate generalizable knowledge to serve the collective good, which is distinct from clinical practice.
In response to Drs Kohrmann and Schwab’s arguments, we are surprised by some of their statements. Although functional outcomes are improved, thrombolysis in ischemic stroke patients has never been shown to reduce mortality.2 Therefore, suggesting that subjecting stroke patients to placebo is akin to euthanasia is inaccurate. In contrast, in cases of malignant infarction (embolic M1 occlusion as mentioned by the authors) hemicraniectomy has been shown to both prevent death and increase the number of patients with a favorable functional outcome.3
Following Kohrmann and Schwab’s argument that recanalization is a prerequisite for a favorable outcome, where does one stop? If a 5.5-hour M1 occlusion (with mismatch) does not recanalize after intravenous therapy, should one proceed with any means necessary to open the vessel? Would we then be “euthanizing” any patient who is delivered to a small-to-medium sized hospital with no timely access to endovascular therapy?
In addition to equipoise, one other principle of ethical clinical research is value. Research has value when the answers to the research question serve a socially valuable purpose. Demonstrating a >3-hour stroke treatment (against a standard-of-care “placebo”), rather than a surrogate marker such as arterial recanalization will lead to a greater societal impact. This is especially true in today’s economic environment where randomized trials proving efficacy are necessary in order to advance guidelines which in turn spur legislation necessary to create and fund stroke networks which provide these capabilities (ie, emergent advanced neuroimaging and rescue endovascular therapy). These steps are crucial as the vast majority of industrialized countries (including the average US community hospital) do not have these capabilities and will require more than opinion to institute change. Similar to the experience in other fields (ie, hormone replacement therapy and cardiovascular events), without randomized trials, healthcare entities will continue to spend unnecessary money and provide treatments that may even be harmful.4
Hacke W, Furlan AJ, Al-Rawi Y, Davalos A, Fiebach JB, Gruber F, Kaste M, Lipka LJ, Pedraza S, Ringleb PA, Rowley HA, Schneider D, Schwamm LH, Leal JS, Söhngen M, Teal PA, Wilhelm-Ogunbiyi K, Wintermark M, Warach S. Intravenous desmoteplase in patients with acute ischaemic stroke selected by MRI perfusion-diffusion weighted imaging or perfusion CT (DIAS-2): a prospective, randomised, double-blind, placebo-controlled study. Lancet Neurol. 2009; 8: 141–150.
Wardlaw JM, Zoppo G, Yamaguchi T, Berge E. Thrombolysis for acute ischaemic stroke. Cochrane Database Syst Rev. 2003; (3): CD000213.
Vahedi K, Hofmeijer J, Juettler E, Vicaut E, George B, Algra A, Amelink GJ, Schmiedeck P, Schwab S, Rothwell PM, Bousser MG, van der Worp HB, Hacke W; DECIMAL, DESTINY, and HAMLET investigators. Early decompressive surgery in malignant infarction of the middle cerebral artery: a pooled analysis of three randomised controlled trials. Lancet Neurol. 2007; 6: 215–222.
Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, Jackson RD, Beresford SA, Howard BV, Johnson KC, Kotchen JM, Ockene J; Writing Group for the Women’s Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results: from the Women’s Health Initiative randomized controlled trial. JAMA. 2002; 288: 321–333.