2.4 Observational studies
Several observational studies compared the two treatment options and reported favourable outcomes for TEVAR for un-TBAD. For example, Qin et al. [30] presented a multicentre retrospective study of 338 un-TABD patients (184 TEVAR and 154 BMT) that ruled in favour of TEVAR. Early events and 30-day mortality were similar between groups while aortic-related adverse events and all-cause mortality were lower with TEVAR (P=0.025 and P=0.01, respectively) relative to BMT. Conversely, Xiang et al. [31] retrospectively analysed data from 357 patients with acute un-TBAD (191 TEVAR and 166 BMT) and indicated that TEVAR was associated with more early complications e.g. acute renal failure, type I endoleak, stroke, rupture, retrograde Type A dissection (RTAD), and organ failure (events occurring in-hospital or within 30 days after diagnosis), but similar 30-day mortality. TEVAR however still improved mid-term survival and decreased risk of late death as well as late aortic ruptures (occurring
>30 days after diagnosis). Freedom from all-cause mortality and aortic-related death were significantly higher with TEVAR; thus, the authors recommended it as first-line treatment for acute un-TBAD [31].
In a meta-analysis, Hossack et al. [18] reported a lower risk of all-cause and aorta-related mortality with TEVAR than BMT (P<0.001 and P=0.001, respectively) for acute and subacute un-TABD. Nevertheless, TEVAR was associated with significantly higher risk of early stroke (P=0.002), but similar inpatient mortality and reintervention rates to BMT. Another meta-analysis by Enezate et al. [19] reported comparable rates of short, intermediate, or mid-term all-cause mortality and aortic dilation between TEVAR and medical therapy in acute dissection. TEVAR yet showed significantly lower 1-year risk of aortic rupture (P=0.01). Chen et al. [32] demonstrated that TEVAR performed in the acute stage of dissection was associated with an increased risk of RTAD.
The prevailing consensus indicates that TEVAR provides comparable benefit to current medical therapies for un-TBAD. Additional research is warranted to determine the potential early, mid-term, and late outcome benefits of TEVAR in un-TBAD to further optimise patient management. A summary of all the above findings can be found in Table 1.
Timing of TEVAR: When to intervene?
Timing of TEVAR for all TBAD has provoked considerable discussion over the last twenty years. However for un-TBAD this does remain a controversial issue as there is always those who suggest TEVAR is unnecessary and optimum treatment in medical therapy alone. For those presenting with a complicated TBAD, treatment by TEVAR is more easily defended. This is due to risk of adverse events both short and long term if intervention by TEVAR is not performed. Intervention in the hyperacute phase by TEVAR is invariably in a high risk situation, where if nothing is done then a significant mortality rate might be expected due to a distinct lack of research. Data on TEVAR timing is varied, herein we seek to analyse and evaluate the current available evidence. These findings are summarised in Table 2.
Most of the data concerning the timing of TEVAR is extracted from studies concerning co-TBAD, while the fate of un-TBADs remains to be established. A retrospective analysis by Lee et al. [33] split 87 patients into acute/subacute (≤6 weeks, n = 35), early chronic (6 weeks to 1 year, n = 20), and late chronic (>1 year, n = 32) groups based on timing of TEVAR after symptom onset of the TBAD. Clinical outcomes including aortic remodelling (maximum total aorta diameter and TL/FL diameters) were similar in the acute/subacute and early chronic phases of TBAD, but superior to those in the late chronic TBAD group. Five-year overall mortality and aorta-related mortality were slightly lower in the acute/subacute and early chronic groups compared to late chronic (2.9% versus 0 versus 12.5%, respectively, P=0.108, and 2.9% versus 0 versus 9.4%, respectively). Desai et al. [34] analysed data from 132 TEVARs out of which 70 were performed within 48 hours of presentation (Acute-Early), 44 performed between 48 hours and 14 days from presentation (Acute-Delayed), and 18 performed between 14 days and 6 weeks of presentation (Subacute). The results demonstrated that earlier intervention with TEVAR was associated with increased periprocedural complications but comparable late outcomes.
The VIRTUE Registry, a prospective, non-randomised multicentre European Clinical Registry focused on 100 patients with acute (n=50), subacute (n=24), and chronic co-TBAD (n=26). Thirty-day mortality and stroke rates were 8%, 0%, and 0% for acute, subacute, and chronic lesions, respectively. Three-year follow-up results showed no difference for all-cause mortality (P=0.20), dissection-related mortality (P=0.48) and overall aortic reintervention (P=0.19) between groups. They observed in acute co-TABD one stroke, one rupture and two RTAD. Notably, no cases of RTAD in the subacute and chronic groups were noted. However, one with a chronic TBAD suffered a rupture on follow up. With regards to FL volume change, this was higher in the acute than in the chronic group (P<0.001) and similar when the subacute and chronic group were compared (P=0.004). However, there was no difference in FL area change between the acute and subacute groups. As a conclusion, the authors stated that the retention of aortic plasticity in the subacute group extends the therapeutic window for TEVAR to 90 days [35][36].
A single centre study by Xie et al. [37] retrospectively examined 267 patients with un-TBAD, carrying risk factors for complications or dissection progression, treated by TEVAR in the acute (1-14 days, n=130) or subacute (15-90 days, n=137) phase. No difference was observed in early outcomes between the groups. However, only those treated acutely suffered aortic rupture, RTAD, and disabling stroke. Interestingly, 30-day mortality in the acute group was five times that of the subacute group (3.8% vs. 0.7%) but not statistically significant (P=0.11), which suggests that intervention timing is not associated with 30-day mortality. Multivariable logistic analyses also suggested that the timing of the TEVAR did not independently correlate with 30-day outcomes. Finally, Xie et al. [37] were unable to reach a definitive consensus but indicated that TEVAR for high risk un-TBAD in the acute phase was associated with a propensity toward higher rates of early complications but comparable late outcomes.
Two studies analysed data from the SVS Vascular Quality Initiative (VQI) TEVAR for TBAD project. Wang et al. [38] reported similar findings to Xie et al. [37] as they could not find clearly defined patterns in mortality or re-intervention associated with timing of TEVAR. The authors stated that intervention during the acute phase of dissection rather than chronic showed a trend towards increased 30-day mortality and decreased freedom from reintervention. Torrent et al. [39] presented similar findings with fewer patients requiring re-intervention within 30 days and one year in the subacute phase relative to the acute phase (P=0.02 and P=0.007, respectively). Crude data prior to propensity matching highlighted an increased mortality within 30 days in the 1-14 day group (7.5% compared to 2.7% in the 15-90 day group, P=0.021). However, multivariate analysis for long-term survival, complications, or long-term reintervention demonstrated no differences. Similar to the two aforementioned studies [37][38], Torrent and colleagues [39] concluded that the timing of intervention does not appear to be independently predictive of mortality or postoperative complications; however, considering whether to intervene in the acute phase is a decision that must be made with much caution.
Miyairi et al. [40] retrospectively investigated 680 patients in Japan over a 5 year time period who underwent TEVAR for TBAD. These were classified as hyperacute (n=295, performed within 24 hours of presentation of symptoms), acute (n=97, 24 hours to 14 days) and subacute (n=288, 14 days to 6 weeks). Primary end point was 30-day operative mortality. Outcomes for TEVAR were worse for hyperacute patients as these had more frequent immediate life-threatening complications such as rupture or malperfusion. Additionally, TEVAR performed acutely did not appear to increase the risk of added complications compared to subacute patients. To further verify this, hyperacute patients had a higher operative mortality and severe complications including aortic dissection compared to acute and subacute (11.9%, 0%, 1.7%; P<0.001; and 32.5%, 10.3%, 8.3%; P<0.001, respectively). Nonetheless, no differences were reported for these outcomes between acute and subacute phases (P=0.191 and P=0.553, respectively).
Finally, literature reviews by Alfson et al. [2] and Matsuda et al. [41] supported TEVAR for un-TABD and discussed timing of intervention. Both concluded that intervention during the subacute phase of TBAD improved survival. Based on this, the subacute phase (14-90 days after symptom onset), appears to be the optimal TEVAR therapeutic window for un-TBAD. However, future randomized control trials and observational studies, investigating TEVAR for un-TBAD need to incorporate timing of intervention into their design to provide more definitive data to further optimise clinical practice and decision making. Also, closer scrutiny of the initial CT scans and clinical presentation may allow accurate initial classification of the TBAD as to whether they are complicated, uncomplicated or high risk uncomplicated. It may well be a significant number may be part of the latter group particularly as is often the case, the disease process is evolving and not clear cut to place into a specific category.
Conclusion
TEVAR has proven to be a safe and effective treatment for un-TBAD in combination with OMT through comparable survival outcomes, improved aortic remodelling, and relatively low periprocedural added risks. Though the timing of intervention remains controversial, it is becoming clear that performing TEVAR during the subacute phase of un-TBAD yields better outcomes compared to earlier and delayed (>90 days) intervention. Further research is required into both short and long-term outcomes of TEVAR in addition to its optimal therapeutic window for un-TBAD. With stronger evidence, TEVAR is likely to be adopted as the gold-standard intervention for un-TBAD with definitive timeframe guidelines.