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We read with interest the editorial by Darsaut and colleagues entitled, “PHASES and the natural history of unruptured aneurysms: science or pseudoscience?”. Beginning with references to Aristotle and Pliny the Elder (always impressive), the authors launch a critique of studies of the natural history of unruptured aneurysms. With attention to ISUIA and the PHASES system, the contributors from Quebec call attention to limitations in both prospective and retrospective studies of the risk of rupture and associated risk factors for rupture of intracranial aneurysms. In their view, these imperfect studies are so deeply flawed that they are essentially useless as tools to inform decision-making with patients with unruptured intracranial aneurysms. Ending with the umpteenth call for a randomized trial, the authors create the impression that, for all patients with all kinds, sizes and locations of intracranial aneurysms, clinicians are powerless to use data from the available studies, condensed in the PHASES Score, to guide decision-making.
The PHASES score, developed from a pooled analysis of six prospective cohort studies of patients with unruptured intracranial aneurysms, was designed to use existing natural history data (limited though that may be), to provide some estimate of future rupture risk and to aid in identifying risk factors for rupture that may push clinician and patient past the treatment threshold. Several lines of evidence support the use of PHASES...
The PHASES score, developed from a pooled analysis of six prospective cohort studies of patients with unruptured intracranial aneurysms, was designed to use existing natural history data (limited though that may be), to provide some estimate of future rupture risk and to aid in identifying risk factors for rupture that may push clinician and patient past the treatment threshold. Several lines of evidence support the use of PHASES in the day-to-day management of patients with unruptured intracranial aneurysms.
First, conservative management of selected unruptured intracranial aneurysms, along with attention to risk factors for growth and rupture, such as hypertension and cigarette smoking, is both widespread and valid. Interesting recent retrospective studies have shed light on both the risk of aneurysm enlargement during serial surveillance imaging (overall annual risk of 2-5%) and whether risk of rupture is elevated in patients with enlargement during surveillance (it is, to the tune of an annual risk of rupture of 18.5%) [3-6]. Thus, although treatment of unruptured aneurysms is extensive worldwide, conservative management is widespread also, and methods to inform decision-making in this setting are much needed.
Second, the authors of the editorial take issue with the limitations and imprecision of both ISUIA and PHASES, stating that “PHASES…has never predicted a single event…” and that three large Japanese cohorts “have refuted the ISUIA predictions.” Although Greving and colleagues did indeed use the unfortunate phrase “prediction of risk” in the title of their paper about PHASES, the actual purpose of PHASES (and ISUIA) was to estimate risk, given patient-specific factors, rather than predict risk. The term predict implies a degree of precision that is not realistic in this setting. Rather, estimations of risk, however flawed and imprecise they are, serve to nudge patients and their clinicians toward one direction or another. In the absence of Level I evidence, black and white decision tools are simply not possible. On the other hand, when an accumulation of factors that are associated with growth and rupture are present in an individual patient, this individual may be inclined to seek treatment, even though a precise “prediction” of rupture risk is not possible.
Lastly, the authors conclude their editorial with a spirited call for a randomized trial. However, it is nearly impossible to imagine that a multicenter randomized trial comparing medical management to treatment of unruptured aneurysms could be accomplished in the current environment. Indeed in a previously published assessment of the failed TEAM Trial, the authors outline three compelling reasons for the futility of any attempt at conducting a randomized trial of unruptured aneurysms: 1) Lack of funding support and bureaucratic barriers from scientific agencies (NINDS, CIHR) 2) Physician unwillingness to enter patients in such a trial due to lack of equipoise, and 3) Patient disinterest in trial participation where a desired intervention would be denied. Unless major changes have occurred in bureaucratic and funding processes, physician opinion, and patient desires in the last few years, we agree with the authors prior work on the futility of hoping for such a trial. Furthermore, any serious attempt at a randomized trial would be at risk of suffering the same fate as the ARUBA trial. Strenuous opposition to ARUBA arose long before trial completion. Objection to ARUBA centered on the argument that a randomized trial of treatment of a life-long condition such as brain AVMs, with only 5-year follow-up, could not fairly compare to interventions with very different risk functions over time. A similar study conducted on unruptured intracranial aneurysms would be hampered by identical limitations.
In the absence of a hypothetical “ideal” study, which the hard nature of reality is unlikely to deliver, clinicians and patients must make decisions, and make them today. PHASES while distinctly not an ideal study, provides guidance based on evidence, when an ideal study is unlikely to be accomplished in the foreseeable future.
1 Darsaut T, Fahed R, Raymond J. PHASES and the natural history of unruptured aneurysms: science or pseudoscience? J Neurointerventional Surg 2016;:neurintsurg–2016.
2 Thompson BG, Brown RD, Amin-Hanjani S, et al. Guidelines for the management of patients with unruptured intracranial aneurysms: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 2015;46:2368–2400.
3 Sonobe M, Yamazaki T, Yonekura M, et al. Small Unruptured Intracranial Aneurysm Verification Study: SUAVe Study, Japan. Stroke 2010;41:1969–77. doi:10.1161/STROKEAHA.110.585059
4 Inoue T, Shimizu H, Fujimura M, et al. Annual rupture risk of growing unruptured cerebral aneurysms detected by magnetic resonance angiography. J Neurosurg 2012;117:20–25.
5 Backes D, Vergouwen MD, Groenestege ATT, et al. PHASES score for prediction of intracranial aneurysm growth. Stroke 2015;46:1221–1226.
6 Serrone JC, Tackla RD, Gozal YM, et al. Aneurysm growth and de novo aneurysms during aneurysm surveillance. J Neurosurg 2016;125:1374–82. doi:10.3171/2015.12.JNS151552
7 Greving JP, Wermer MJ, Brown RD, et al. Development of the PHASES score for prediction of risk of rupture of intracranial aneurysms: a pooled analysis of six prospective cohort studies. Lancet Neurol 2014;13:59–66.
8 Raymond J, Darsaut TE, Molyneux AJ. A trial on unruptured intracranial aneurysms (the TEAM trial): results, lessons from a failure and the necessity for clinical care trials. Trials 2011;12:64.