Association of Mortality and Acute Aortic Events With Ascending Aortic Aneurysm

Key Points Question What are the growth rate and risk of complications in patients with moderately dilated ascending aortas? Findings This systematic review and meta-analysis of 20 studies including 8800 patients found that the ascending aorta growth rate was 0.61 mm/y, and the incidence of elective aortic surgery was 13.82%. The linearized mortality rate was 1.99% per patient-year, while the rate of aortic dissection, aortic rupture, and mortality was 2.16% per patient-year. Meaning More robust natural history data from prospective studies are needed to better inform clinical decision making in patients with ascending aortic aneurysms.


Introduction
Ascending aortic aneurysm (AsAA) is generally indolent and asymptomatic until presentation with catastrophic complications of rupture and dissection. When a rupture or dissection occurs, it is fatal in a large proportion of patients prior to hospital presentation. Those who present to the hospital require an emergency surgical procedure that carries a mortality risk of approximately 20%; in contrast, elective ascending aortic replacement carries a relatively low risk of mortality and morbidity. 1 The goal of elective surgical intervention, therefore, is to provide a survival benefit by replacing the aneurysmal segment of the ascending aorta prior to the occurrence of an acute aortic event. A complete understanding of the natural history of AsAA is critical in determining the risk to benefit ratio of elective aortic surgery.
Aortic diameter is currently the primary variable by which the risk of dissection, rupture, and death is estimated. Existing guidelines recommend surgical repair of asymptomatic AsAA with either tricuspid aortic valve (TAV) or bicuspid aortic valve (BAV) measuring 55 mm or greater in patients without connective tissue disorders, family history, or rapid growth (class I, level of evidence C). 2,3 These recommendations are largely based on expert consensus and a small number of observational studies.
The purpose of this study is to examine the natural history of AsAA by conducting a systematic review and meta-analysis focusing on end points including all-cause mortality, incidence of ascending aortic dissection or rupture, incidence of elective ascending aortic repair, and aortic growth rate.

Study Selection
An online search of Ovid MEDLINE (January 1, 1946, to May 31, 2017) and Embase (January 1, 1974, to May 31, 2017) was conducted by 1 of us (M.G.) using the Meta-analysis of Observational Studies in Epidemiology (MOOSE) reporting guideline; no search software was used. 4 The search was conducted with the following search terms: aortic aneurysm* or aortic aneurysm, thoracic/ or aortic diseases or degenerative aneurysm or aorta/thoracic/ or aortopath* or bicuspid aortic valve or BAV or bicuspid aortopath* or BAV association* AND size or growth or medical* or nonsurgical* or unoperated AND natural history or survival or rupture or aortic rupture or dissection. The search was limited to English language publications, resulting in a total of 7196 articles following removal of 2751 duplicates. Two additional studies were identified through a reference search for a total of 7198 studies for initial review.
A study was eligible for inclusion if it reported growth rate, rate of dissection or rupture, or all-cause mortality of patients with AsAA. Exclusion criteria included the following: (1) studies that considered all thoracic aortic aneurysms from various regions (ascending, arch, descending thoracic, and thoracoabdominal) as 1 entity; (2) studies of heritable aortic aneurysms associated with genetic causes, such as Marfan syndrome; (3) studies including nonaneurysmal aortas; (4) studies in which mean patient age was less than 16 years; (5) studies limited to patients with acute aortic syndromes; and (6) editorials, commentaries, case reports, studies with small cohorts (N < 10), and review articles. Reference lists of the included articles were also screened to identify relevant articles. Contact of authors was not required for clarification of the published data. Study selection was done by 2 of us (M.G. and H.N.S.) separately.

Data Extraction
Two of us (M.G. and H.N.S.) independently extracted relevant data for all studies with a standardized data extraction form; the data extracted were then compared, and all discrepancies were resolved by consensus. Data extraction included demographics, study design, sample size, follow-up, patient risk factors and comorbidities, initial aneurysm diameter, aneurysm growth rate over the follow-up period, incidence of dissection or rupture, size at dissection or rupture, incidence of elective ascending aortic surgery, and all-cause mortality. For studies that were published from the same center for the same patient population, the publication with the longest patient-year follow-up was included in the meta-analysis.

Statistical Analysis
Studies that did not report on a specific outcome measure were excluded from analysis of that outcome. Summary effect measures for growth rate, incidence of elective aortic repair, aortic dissection or rupture, and all-cause mortality were obtained by logarithmically pooling data with an inverse-variance weighted random-effects model. 5 The summary effects measures were presented with a 95% confidence interval. When the incidence of an end point was reported as 0, the value was adjusted to an event rate of 1/4 × sample size to permit computation in the random-effects model. To stabilize the variance of a proportion outcome, data underwent the Freeman-Tukey double arcsine transformation. 6 The incidence of elective aortic repair was presented as a percentage, while all-cause mortality, aortic dissection, and aortic rupture were linearized (percentage per patient-year). A composite linearized outcome of all-cause mortality or aortic dissection or rupture was also evaluated. Metaregression analysis was performed to examine relationships between studylevel characteristics, including year of study completion, mean initial aneurysm size, valve type groups, and outcomes. Heterogeneity of the summary effects measures was assessed with the I 2 test and considered present when I 2 was greater than 50%. A 2-sided P value of less than .05 was considered statistically significant.

Results
The primary search resulted in 7198 studies after removal of duplicates. Of these, 7136 articles were excluded based on title or abstract, and full-text review was completed on 62 studies (Figure 1). The following were then excluded: studies that considered AsAA, arch aneurysm, and descending thoracic aneurysm as a single entity, retrospective analyses of an aortic dissection database, biomechanical or population-based studies that only reported prevalence of the disease rather than its natural history, studies with duplicate cohorts, studies on BAVs without concomitant AsAA, studies on natural history of aortic root or sinus of Valsalva, studies on genetic analysis and mathematical modeling of AsAA, and studies on arch aneurysms only.

Study Characteristics
Twenty studies published from January 1, 1964, to December 31, 2017, including a total of 8800 patients, were included in the systematic review and data analysis. [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26] The total follow-up time was 31 823 patient-years. The studies were divided into 4 groups: AsAA with TAV with or without previous aortic valve replacement, AsAA with native BAV, mixed valve type that included AsAA with either TAV or BAV, and studies that did not specify the valve type. Studies that did not specify valve type did not state explicitly whether aneurysms of hereditary etiologies were excluded. Four studies clearly separated patients with TAV and BAV, and the data were collected separately. The The mean (SD) age of the study patients was 57.75 (9.47) years and 6653 (75.6%) were male.
Fourteen studies reported the incidence of elective aortic surgery during follow up, 12 studies reported incidence of aortic dissection or rupture, and 13 studies reported the incidence of all-cause mortality over follow-up periods that ranged from 2.5 to 16.0 years. The pooled incidence of elective aortic surgery was 13.82% (95% CI, 6.45%-21.41%; I 2 = 56%) over a median (range) follow-up of 4.2 (2.9-15.0) years (Figure 3; eAppendix 2 in the Supplement). For patients with AsAA with TAV, the pooled incidence of elective aortic surgery was 5.50% (95% CI, −0.57% to 11.69%; I 2 = 99%), while for patients with AsAA with BAV, the pooled incidence of elective aortic surgery was 20.66% (95%

Discussion
In this study, we sought to explore the natural history of AsAA and to compare outcomes based on valvular phenotype. However, because all except 2 studies followed thoracic aortic management guidelines for ascending aortic repair when patients met criteria for surgical intervention, the true natural history of AsAA across the size spectrum was not examined; instead, we reported on the growth rate; the incidence of aortic repair, dissection, and rupture; and all-cause mortality of AsAA followed in the real-world clinical setting.
The growth rate of the moderately dilated aorta is low, and differences do exist between the different valves types, with large intragroup variation as well (Figure 2). For patients with TAV only, the pooled mean annual growth rate was only 0.34 mm/y, compared with 0.76 mm/y for patients with BAV only. However, this difference was not statistically significant. In both groups, the annual growth rates reported by Davies et al 10 (1.3 mm/y for the TAV group and 1.9 mm/y for the BAV group) were considerably higher than those reported by other studies in the same group; other studies reported an annual growth rate between −0.6 mm/y and 0.75 mm/y for the TAV group and 0.22 mm/y and 0.9mm/y for the BAV group. The low mean growth rate may have implications for appropriate time interval between imaging studies for follow-up of patients with moderately dilated ascending aorta. Current guidelines suggest annual or biannual imaging for patients with AsAA.
Gagné-Loranger et al 14 argued that contrary to guideline recommendations for follow-up for patients with AsAA, annual or biannual imaging may not be cost-effective. The result of the meta-analysis supports this proposition; however, there are a lack of consistent data that inform the timing in which more frequent follow-up is required. Interestingly, there was a significant difference in the pooled mean annual growth rate between the mixed valve type group and the nonspecified valve type group (0.31 mm/y vs 1.05 mm/y, respectively, P < .05). This may represent the inclusion of genetic conditions in the nonspecified valve type group that was not specifically stated within the inclusion and exclusion criteria of the studies, and therefore was not excluded from the systematic review. There was also significant interstudy variation in all outcomes examined. There was a nonsignificant trend toward higher rate of elective aortic repair in studies reporting on patients with BAV only compared with patients with TAV only (20.66% vs 5.50%, respectively, P = .11). However, similar to the data for growth rate, the incidences of elective ascending aortic surgery in the TAV group and BAV group reported by Davies et al 10 again appeared to be outliers at 44.79% (95% CI, 40.20%-49.38%) and 72.85% (95% CI, 62.44%-83.27%), respectively, when compared with other studies (Figure 3), especially those with similar initial mean aneurysm diameter, such as those reported by Gaudino et al, 21 La Canna et al, 9 and Michelena et al. 25 The linearized rate of composite outcome of 3.39% per patient per year for the TAV group was also much higher compared with other groups, as was the pooled estimate of 2.16% per patient per year (Figure 4). Notably, the rate of composite outcome reported by Davies et al is higher not only when compared with reports with similar initial aneurysm diameter, but also when compared with the rate reported by Joyce et al,7 which included patients who were considered nonoperative with an aneurysm size of more than 5.5 cm.
Factors associated with annual growth rate not only varied significantly but were often contradictory between studies; therefore, meaningful statistical analysis evaluating their association with outcomes could not be performed. While 3 studies 8,17,19 identified baseline aortic diameter as a factor associated with increased growth rate, 4 studies 13,14,18,24 found that baseline aortic diameter was not associated with aortic dilatation, and 2 studies 12,16 reported higher annual aortic growth rate  with lower baseline aortic diameter. One study 10 found that aortic stenosis is associated with higher annual aortic dilatation, while another 17 found aortic regurgitation to be associated with higher growth rate. Another study 26 determined that valvular dysfunction is not associated with faster aortic dilatation. Renal failure and female sex were identified as being associated with faster annual growth rate in 2 separate studies, 14,16 while anticoagulation and statin medication use were found be associated with a lower growth rate. 11,13 In addition, factors associated with increased risk of dissection and rupture were poorly reported. Coady et al 27 and Vapnik et al 15 demonstrated that size was the most important factor associated with acute dissection or rupture; however, most other studies did not report aneurysm size at aortic dissection or rupture, and comparison was therefore not possible.
Current guidelines for surgical thresholds for AsAA are based largely on expert consensus and retrospective observational studies with inconsistent data. In contrast, treatment guidelines for abdominal aortic aneurysm (AAA) are founded on extensive data and are widely accepted by the surgical community. Multiple large, multicenter randomized clinical trials that included more than 200 000 patients established the natural history of small AAA (<55 mm) as well as proper surveillance for patients with this life-threatening disease. [28][29][30][31][32] By comparing long-term outcomes of patients randomized to either the surveillance group (surgery if aneurysm size is >55 mm or growth rate is >10 mm/y) or the early surgery group, the trials have shown that for AAA smaller than 55 mm, the risk of early surgery outweighs the risk of rupture during surveillance and that women have a higher risk of rupture than men. On the other hand, the natural history of large AAA (>55 mm) has also been explored in prospective studies in which patients with AAA larger than 55 mm who were not suitable surgical candidates were followed. [33][34][35] Although most studies confirmed that large AAA has a higher rupture rate than small AAA, controversies exist on whether the difference in rupture rate reflects the difference between patients at high operative risk with severe comorbidities and the The dashed line is a reference line demarcated at the combined summary estimate and provides a visual reference comparing the subgroup summary estimate with the combined summary estimate. Error bars indicate 95% CIs. BAV indicates bicuspid aortic valve; TAV, tricuspid aortic valve.