Difference in rupture risk between familial and sporadic intracranial aneurysms: an individual patient data meta-analysis

Objective: We combined individual patient data (IPD) from prospective
cohorts of patients with unruptured intracranial aneurysms (UIA) to assess
to what extent patients with familial UIA have a higher rupture risk than
those with sporadic UIA. Methods: For this IPD meta-analysis we performed
an Embase and Pubmed search for studies published up to December 1, 2020.
We included studies that 1) had a prospective study design; 2) included 50
or more patients with UIA; 3) studied the natural course of UIA and risk
factors for aneurysm rupture including family history for aneurysmal
subarachnoid haemorrhage and UIA; and 4) had aneurysm rupture as an
outcome. Cohorts with available IPD were included. All studies included
patients with newly diagnosed UIA visiting one of the study centers. The
primary outcome was aneurysmal rupture. Patients with polycystic kidney
disease and moyamoya disease were excluded. We compared rupture rates of
familial versus sporadic UIA using a Cox proportional hazard regression
model adjusted for the PHASES score and smoking. We performed two
analyses: 1. only studies defining first-degree relatives as parents,
children, and siblings and 2. all studies, thus both including and
excluding siblings as first-degree relatives. Results: We pooled IPD from
eight cohorts with a low and moderate risk of bias. First-degree relatives
were defined as parents, siblings and children in six cohorts (29% Dutch,
55% Finnish, 15% Japanese), totalling 2,297 patients (17% familial, 399
patients) with 3,089 UIA and 7,301 person-years follow-up. Rupture
occurred in 10 familial patients (rupture rate: 0·89%/person-year; 95%
CI:0·45-1·59) and 41 sporadic patients (0·66%/person-year; 95%
CI:0·48-0·89); adjusted HR for familial patients 2·56 (95% CI: 1·18–5·56).
After adding also the two cohorts excluding siblings as first-degree
relatives resulting in 9,511 patients the adjusted HR was 1·44 (95% CI:
0·86–2·40). Conclusion: The risk of rupture of UIA is two and a half times
higher, with a range from a 1.2 to 5 times higher risk, in familial than
in sporadic UIA. When assessing the risk of rupture in UIA, family history
should be taken into account.