The Quest for Precision Medicine: Towards a “Standard Model” of Aneurysm Risk Prediction
El Ahmadieh, Tarek Y.; El Tecle, Najib E.; Lall, Rohan R.; Wong, Albert P.; Bendok, Bernard R.
The Standard Model in physics has been touted as a model that when fully understood can explain the Universe.1,2 An incomplete understanding of subatomic particle behavior remains a barrier to fully elucidating the Standard Model.1,2 Similarly, understanding all the factors that contribute to aneurysm rupture risk prediction in any given individual, could lead to more precise prediction of individual aneurysm behavior consistent with the goals of “Precision Medicine.”3 While current advances in surgical and endovascular techniques allow safe treatment options of most aneurysms, the increasing number of unruptured intracranial aneurysms (UIAs) being detected raises new questions regarding the appropriate indications for intervention. Current natural history studies report an overall annual risk of rupture ranging between 0.8% and 1.4% (follow-up <5 years).4-9 Risk factors associated with aneurysm rupture vary among different studies, but mainly include cigarette smoking, aneurysm size, location, and morphology, as well as the presence of multiple aneurysms and a previous history of subarachnoid hemorrhage (SAH).4-9 A more precise understanding of the behavior of UIAs and the risk factors associated with their rupture remains crucial for better patient counseling. To study the long-term natural history of UIAs and to further identify independent risk factors predictive of aneurysm rupture, Juvela et al. conducted a retrospective review of a prospectively collected database including patients who were diagnosed to have UIAs between 1956 and 1978 and were followed conservatively until they experienced SAH or death, or up to 2012. The results of the study are published in the July 2013 issue of Stroke.10
Between 1956 and 1978, a total of 142 patients were diagnosed with 181 UIAs at the department of Neurological surgery, Helsinki University Central Hospital, Finland. Of these patients, 131 presented with a ruptured intracranial aneurysm and were found to have additional UIAs (92.2%), 5 presented with incidentally discovered UIAs (3.5%), and 6 presented with symptomatic UIAs (4.2%). All patients were followed up until they experienced SAH or death, or up to 2012. Patients who initially presented with SAH had their ruptured aneurysm clipped and were followed for rupture of any additional UIAs. Baseline characteristics of all patients were obtained from medical records prior to follow-up. Two prior follow-up reports on the behavior of UIAs in this cohort were published in 1993 and 2000.11,12 Between 2011 and 2012, the authors performed another long-term follow-up study of the natural history of UIAs in the same cohort. This was performed using a phone-based questionnaire to which patients themselves or patient relatives responded. Information on all patients was obtained including data on their body mass index, medical history (including hypertension) and hospital visits, regular medication, alcohol consumption status, cigarette smoking status, and family history of ruptured aneurysms. This information was further confirmed by reviewing medical records of other hospitals and reports of primary care physicians.
At the conclusion of the study, 34 out of the 142 patients experienced a SAH (24%). This led to an overall estimated annual rupture rate of 1.1%. The mean follow-up time per patient was 21.6 years. The average rupture rates for patient groups who presented with incidental UIAs, symptomatic UIAs, and prior SAH were 0.8%, 2.2%, and 1.1% per year, respectively (Table 1). Compared to the last follow-up study in 2000, the risk of aneurysm rupture decreased significantly suggesting that the risk of bleeding decreases with very long-term follow-up (0.3% per year; only 1 out of 40 patients who remained alive after 2000 experienced aneurysm rupture). Additionally, the risk of rupture was found to maintain a constant level for a shorter period of time in elderly patients (>50 years) compared to younger patients (10 years vs. 25 years, respectively).
In this study, independent risk factors for aneurysm rupture included current cigarette smoking, aneurysm size (≥7mm), younger age (<50 years), and anterior communicating artery location. Hypertension and alcohol consumption were found to increase the risk of rupture, but did not reach statistical significance. When tested as a time-dependent covariate, continuation of smoking was noted to be a more significant risk factor for aneurysm rupture compared to current smoking (relative risk: 3.04; P = .020). This observation further emphasizes the importance of smoking cessation for patients with UIAs. The presence of multiple aneurysms and a prior history of SAH were not found to be significant risk factors of aneurysm rupture in this study. The authors suggest that younger patients (<50 years) with UIAs should, if possible, receive treatment regardless of the aneurysm size. They also suggest that younger patients, who have no history of smoking, should still be considered for aneurysm treatment given the high success rates of current open and endovascular techniques and the potentially disastrous outcomes of SAH.
Despite the limitations of the current study, the reported findings are worthy of note. Ultimately, each patient should be approached individually, taking into consideration all potential risk factors of aneurysm rupture and balancing the risks of any intervention against the risks of conservative management. Genetics, aneurysm wall histology, and aneurysm hemodynamics are additional potentially important players in the complex and yet elusive aneurysm risk prediction model.
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