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Randomized clinical trials: the double edged sword
  1. J Mocco1,
  2. Cian O'Kelly2,
  3. Adam Arthur3,
  4. Phil M Meyers4,
  5. Joshua A Hirsch5,
  6. Henry H Woo6,
  7. Peter A Rasmussen7,
  8. Felipe C Albuquerque8,
  9. Aquilla Turk9,
  10. Rob Tarr10,
  11. David Fiorella6
  1. 1Department of Neurosurgery, Vanderbilt University Medical Center, Nashville, Tennessee, USA
  2. 2Department of Neurosurgery, University of Edmonton, Edmonton, Alberta, Canada
  3. 3Department of Neurosurgery, Semmes-Murphey Neurologic and Spine Institute and Mid-South Imaging and Therapeutics, Memphis, Tennessee, USA
  4. 4Department of Neurosurgery and Radiology, New York Presbyterian Hospital, Columbia University, College of Physicians and Surgeons, Neurological Institute, New York, New York, USA
  5. 5Department of Radiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
  6. 6Department of Neurosurgery, Cerebrovascular Center, State University of New York at Stony Brook, Stony Brook, New York, USA
  7. 7Department of Neurosurgery, Cleveland Clinic Foundation, Cleveland, Ohio, USA
  8. 8Department of Neurosurgery, Barrow Neurological Institute, Phoenix, Arizona, USA
  9. 9Department of Radiology, Medical University of South Carolina, Charleston, South Carolina, USA
  10. 10
  1. Correspondence to Dr D Fiorella, Department of Neurosurgery, Cerebrovascular Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8122, USA; David.Fiorella{at}sbumed.org

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“Evidence based medicine has contributed to the development of a rigid hierarchy of research design that underestimates the limitations of randomized controlled trials”1

J Concato

A Randomized Trial of Unruptured Brain Arteriovenous Malformations

In May 2013, the Data Safety Monitoring Board of A Randomized Trial of Unruptured Brain Arteriovenous Malformations (ARUBA) halted enrollment due to excess morbidity in the interventional group. This result was not surprising to the medical community, as prior editorials attest.2 Until complete trial data are available, it is impossible to determine why interventional treatment was deemed inferior to medical management. However, the trial had major inherent limitations that portended failure from the outset.

Brain arteriovenous malformations (AVMs) are congenital lesions, which frequently present in young patients. The goal of treatment is a complete and durable cure, with limited neurological morbidity and mortality, and a better quality of life, for the rest of that patient's life. Unfortunately, the logistics of any trial, particularly a National Institutes of Health funded trial, initially will only accommodate follow-up for a finite period of time—5 years in the case of ARUBA. With this study design, patients allocated to intervention were exposed to the entire upfront risk of the interventional procedure(s) to achieve curative treatment of the lesion. While most patients allocated to intervention presumably underwent definitive treatment and were cured of the AVM during the trial, the benefit of this curative treatment was only realized for the relatively brief period of follow-up. At the same time, patients allocated to the medical management arm, who remain at a lifelong risk for neurological morbidity, were only tracked for a small fraction of their ‘at risk’ period. For this reason, the study design heavily favored medical management. In other words, patients undergoing treatment face the full risk posed by that treatment during the study while those allocated to medical management are …

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