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Are placebo‐controlled trials ethical in areas where current guidelines recommend therapy? Yes

This question has arisen following the publication of the ARTEMIS study; a placebo controlled study of fondaparinux for the prevention of venous thromboembolism (VTE) in medical patients [1]. There are a number of issues surrounding the use of a placebo control group including: having a group that represents the standard of care ; the relationship between research ethics and integrity; and the principles of minimizing risks. These issues are relevant in areas where guidelines both do and do not recommend therapy.We kept these issues in mind when we designed the ARTEMIS study. The issue of treatment of the control group in clinical trials is one of the most heated debates in international research ethics. The debate has centered on the controversial level of treatment that has been called standard of care . However, there is not only disagreement about the quality of the care that has to be supplied, but also there is no widely accepted clear meaning of this concept. This is particularly important where research ethics and research integrity discourses overlap: firstly, because the choice of a control group (e.g. placebo control) is a key ethical issue related to the protection of the research subjects interests; secondly, because the quality of the research data, that is one of the key elements of research integrity, is closely connected to the choice of research methodology as well; finally, the principle of minimizing risks and balancing of risks and benefits, one of the main requirements of research ethics, must be taken into account. When planning this study in 2000–2001, the ARTEMIS Trial steering group was extremely aware of the American College of Chest Physicians (ACCP) 2001 recommendations about prophylaxis in medical inpatients, and the important ethical dimensions of this trial [2]. It also considered the position on placebo-controlled trials expressed in the then latest update of the Helsinki Declaration [9]. The group was acutely aware, also, of results from the recently publishedMEDENOX study where thrombosis frequencies, consistent with moderate risk, were 15% in the placebo group and unexpectedly the same in the 20 mg day enoxaparin group [3]. The frequency was reduced to 5.5% in the 40 mg/day enoxaparin group. Afterweighing at length the pros and cons, the steering group accepted a placebo-controlled design for ARTEMIS because this would add clinical value, both to the patients and to the body of research data. The patients, who would have otherwise been deemed not to be at risk and not given thromboprophylaxis, were followed more carefully and underwent venography and early diagnosis and treatment of thrombosis. Supporting arguments considered at the time included the following: 1. Predicting a baseline thrombosis rate for patients enrolled in ARTEMIS would be difficult for several reasons. Risk factors for thrombosis in medical inpatients were poorly defined, it was important that patient selection criteria should be simple and easily applied to routine clinical practice, this meant they would need to differ from those used in previous trials. Furthermore, clinical practice standards required that patients considered by clinicians to be at high risk should be offered prophylaxis known to be effective and should not be enrolled. These different inclusion criteria and the exclusion of high-risk patients made the 10–14% placebo group thrombosis rate estimated when calculating sample size no more than a rough guess. 2. The baseline thrombosis rate is critical for estimating number needed to treat and (at least equally important) to harm. If baseline risk is uncertain, then benefit cannot be judged from active controlled comparisons, as results like those of standard therapy would have no meaning if a low baseline risk is unrecognized (5% event rates in two active treatment groups mean nothing if the baseline rate is also 5%). Regarding harm, there were (and are) concerns about bleeding risk when elderly inpatients with multiple comorbidities and comedications are given anticoagulants like lowmolecular weight heparins (LMWH) (and fondaparinux) that are largely or wholly renal cleared. Again, these concerns could not be addressed without the baseline provided by a placebo treated comparison group. Correspondence: Ander Cohen, Vascular Department, Vascular Medicine Group, King’s College Hospital, London SE5 9RS, UK. Tel.: +44 20 3299 3015; fax: +44 20 7346 3927; e-mail: alexander. cohen@kcl.ac.uk Journal of Thrombosis and Haemostasis, 4: 2130–2132