Unruptured intracranial aneurysms: why we must not perpetuate the impasse for another 25 years We read with interest the Article by Greving and colleagues1 that analysed individual patient data pooled from six cohort studies on the natural history of unruptured intracranial aneurysms (UIAs) and proposed a prognosis score to guide clinicians’ decision-making. No one knows how best to manage these patients (an estimated 2–5% of the adult population), but with the increasing accessibility of non-invasive imaging, physicians are increasingly faced with the dilemma of what to do. One stance maintains that the only acceptable rationale for a preventive treatment is randomised evidence that therapy does more good than harm. Thus, a randomised trial showing better outcomes for treated patients compared with conservatively managed patients would be necessary to justify invasive treatment of UIAs. However, this trial has not yet been successfully completed.2 A different approach is to use observational studies of untreated patients to estimate the natural history of UIAs, and to use this information to inform clinical decisions. Unfortunately, this approach is scientiﬁcally ﬂawed and widespread use of this misleading natural history premise will inevitably delay the work that needs to be done to answer the burning question. But let us, once again, dispassionately examine how this approach fares. All of the available literature for UIAs comprises 8382 patients followed up prospectively. By comparison, an estimated 60 000 patients were treated between 2001–08 in the USA alone.3 In their study, Greving and colleagues pooled the ISUIA study (1691 patients),4 a study from the Netherlands (93 patients), one from www.thelancet.com/neurology Vol 13 June 2014
Finland (142), and three from Japan, including the UCAS study5, with the UCAS accounting for 84% of the Japanese cohort (6513 patients), and collected data from patients followed for varying periods of time (months to ﬁve decades). 230 haemorrhagic events were recorded. Such a number of events necessarily restricts the number of legitimate subgroups that can be created: should 230 events be dissected into 192 different categories, as the authors propose in ﬁgure 2?1 All cohorts were registries of patients selected to be observed, but an important proportion of patients were treated “at the physician’s discretion” during follow-up. The study by the UCAS investigators is a good example of attrition bias, because less than a third (29%) of UCAS patients (1930 of 6697) were observed during the entire follow-up; the other two-thirds of patients were lost to follow-up or crossed over to treatment.5 Undoubtably, the decision to treat patients is likely to have been affected by the same prognostic factors the authors wish to study. Thus, this probably distorts, perhaps severely, the prognostic score. A generous interpretation of the PHASES1 study is that the authors have identified five risk factors (age ≥70 years, hypertension, size >7 mm, subarachnoid haemorrhage from another aneurysm, and location), all with modest relative risks (RRs; between 0·7 and 2·6). For at least three of these factors (age, size, location), treatment risks are also increased, with RRs of the same magnitude.6–8 Size also affects treatment efficacy, raising further doubts on the appropriateness of therapy in the very same patients alleged to be at increased risk of rupture. A safer interpretation could go as follows: UIAs can rupture, but the risk is small, around 1% per year or less. Clearly, larger aneurysms rupture more frequently, but treatment risks
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and eﬃcacy are also aﬀected by size. Hypertension should be treated medically, and not only to serve to justify risky interventions. The reputed increased risks of Japanese and Finnish patients may be explained by various selection biases and differences in methods. There is little doubt that some clinicians will use the proposed score to justify the preventive interventions they undertake. Confronted with a potentially life threatening dilemma, attempts to ﬁnd an expedient solution by redoing meta-analyses of poor quality observational studies might be comforting to those who believe that we need to make choices to act now, no matter how misleading our evidence might be. But this option is how we can perpetuate the impasse for another 25 years. Thankfully, there is another option. For this field to progress, we must accept that treatment recommendations should be tested with a properly designed randomised trial before becoming practised wide scale. While awaiting a verdict, optimum medical care is the care provided within a trial. We declare that we have no competing interests. JR is principal investigator for the Patient Prone to Recurrence after Endovascular Treatment (PRET-2) trial (NCT00626912) and Stenting in the Treatment of Aneurysm (STAT) trial (NCT01340612). TD is principal investigator for the Canadian UnRuptured Endovascular Versus Surgery Trial (CURES) trial (NCT01139892).
*Olivier Naggara, Tim Darsaut, Denis Trystram, Lambros Tselikas, Jean Raymond [email protected]
Department of Neuroradiology, Paris-Descartes University, Centre Hospitalier Sainte-Anne, INSERM UMR894, 75014 Paris, France (ON, DT, LT); Division of Neurosurgery, Department of Surgery, University of Alberta Hospital, Mackenzie Health Sciences Centre, Edmonton, Alberta, Canada (TD); and International Consortium of Neuroendovascular Centres, Interventional Neuroradiology Research Unit, Department of Radiology, University of Montreal, CHUM Notre-Dame Hospital, Montreal, QC, Canada (JR) 1
Greving JP, Wermer MJ, Brown RD Jr, 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. 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. Brinjikji W, Rabinstein AA, Nasr DM, Lanzino G, Kallmes DF, Cloft HJ. Better outcomes with treatment by coiling relative to clipping of unruptured intracranial aneurysms in the United States, 2001-2008. AJNR Am J Neuroradiol 2011; 32: 1071–75. International Study of Unruptured Intracranial Aneurysms Investigators. Unruptured intracranial aneurysms—risk of rupture and risks of surgical intervention. N Eng J Med 1998; 339: 1725–33. Morita A, Kirino T, Hashi K, et al. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med 2012; 366: 2474–82. Kotowski M, Naggara O, Darsaut TE, et al. Safety and occlusion rates of surgical treatment of unruptured intracranial aneurysms: a systematic review and meta-analysis of the literature from 1990 to 2011. J Neurol Neurosurg Psychiatry 2013; 84: 42–48. Naggara ON, Lecler A, Oppenheim C, Meder JF, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: a systematic review of the literature on safety with emphasis on subgroup analyses. Radiology 2012; 263: 828–35. Naggara ON, White PM, Guilbert F, Roy D, Weill A, Raymond J. Endovascular treatment of intracranial unruptured aneurysms: systematic review and meta-analysis of the literature on safety and eﬃcacy. Radiology 2010; 256: 887–97.
Authors’ reply We thank Olivier Nagarra and colleagues for their interest in our pooled analysis of individual patient data on risk of rupture.1 Their comments focus on insufficient evidence from randomised clinical trials for prophylactic vascular interventions of unruptured 538
intracranial aneurysms. The Trial on Endovascular Aneurysm Management (TEAM) was such an enterprise that failed because of poor recruitment.2 We agree that treatment recommendations ideally should be assessed in properly designed randomised clinical trials. However, whether such a trial could be accomplished for unruptured intracranial aneurysms is unclear. Our study showed that in populations from North America and European countries other than Finland, most aneurysms have a very small (3% risk in 5 years), a trial of endovascular or surgical intervention would also be challenging because of the concern about risk of rupture, and many patients and providers would not agree to randomisation. Some have also argued that the intervention techniques used during a trial could already have become outdated by the trial’s conclusion, which precludes the results from being generalisable to future practice. How should we proceed in the assessment of the effectiveness of endovascular and surgical interventions for aneurysms with a high risk of rupture? First, we should have better risk predictions for complications of interventions. These predictions lag far behind the risk predictions of rupture. Second, once valid contemporary aneurysm site-specific and size-specific interventional treatment outcome data are available, we propose to use decision analytical techniques to determine which patients with unruptured intracranial aneurysms
would beneﬁt from an endovascular or surgical intervention.3 The PHASES score can then be used to quantify risks of rupture for these decision models. For now, although there are some limitations, the PHASES score can be used to better deﬁne the risk of rupture and to weigh these risks against the undetermined risks and effectiveness of endovascular or surgical interventions in terms of the prevention of future rupture. We declare that we have no competing interests.
*Jacoba P Greving, Marieke J H Wermer, Gabriël J E Rinkel, Ale Algra [email protected]
Julius Center for Health Sciences and Primary Care (JPG, AA), Department of Neurology and Neurosurgery, Brain Center Rudolf Magnus (AA, GJER), University Medical Center Utrecht, Utrecht, Netherlands; and Department of Neurology, Leiden University Medical Center, Leiden, Netherlands (MJHW) 1
Greving JP, Wermer MJ, Brown RD Jr, 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. 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. Greving JP, Rinkel GJ, Buskens E, Algra A. Cost-eﬀectiveness of preventive treatment of intracranial aneurysms: new data and uncertainties. Neurology 2009; 73: 258–65.
Developing biomarkers for cerebral amyloid angiopathy trials: do potential disease phenotypes hold promise? We read with great interest the Review by Steve Greenberg and colleagues1 about possible outcome markers in disease-modifying trials of cerebral amyloid angiopathy. Sporadic cerebral amyloid angiopathy is generally identified in elderly people and is characterised by the accumulation of amyloid β in cortical www.thelancet.com/neurology Vol 13 June 2014