Abstract
Background: There is emerging evidence to support pre-emptive thoracic endovascular aortic repair (TEVAR) intervention for uncomplicated type B aortic dissection (unTBAD). Pre-emptive intervention would be particularly beneficial in patients that have a higher baseline risk of progressing to complicated TBAD (coTBAD). There remains debate on the optimal clinical, laboratory, morphological and radiological parameters which would identify the highest-risk patients that would benefit most from pre-emptive TEVAR.
Aim: This review summarises evidence on the clinical, laboratory, and morphological parameters that increase the risk profiles of unTBAD patients.
Methods: A comprehensive literature search was carried out on multiple electronic databases including PubMed, EMBASE, Ovid and Scopus in order to collate all research evidence on the the clinical, laboratory, and morphological parameters that increase the risk profiles of unTBAD patients
Results: At present, there are no clear clinical guidelines using risk-stratification to inform the selection of unTBAD patients for TEVAR. However, there are noticeable literature trends that can assist with the identification of the most at-risk unTBAD patients. Patients are at particular risk when they have refractory pain and/or hypertension, elevated C-reactive protein (CRP), larger aortic diameter and larger entry tears. These risks should be considered alongside factors that increase the procedural risk of TEVAR to create a well-balanced approach. Advances in biomarkers and imaging are likely to identify more pertinent parameters in future to optimise the development of balanced, risk-stratified treatment protocols.
Conclusion: There are a variety of risk profiling parameters that can be used to identify the high-risk unTBAD patient, with novel biomarkers and imaging parameter emerging. Longer-term evidence verifying these parameters would be ideal. Further randomized controlled trials and multicentre registry analyses are also warranted to guide risk-stratified selection protocols.
Keywords: Type B Aortic Dissection, Aortic Dissection, Aneurysm, Aortic Surgery
Introduction
Uncomplicated type B aortic dissection (unTBAD) is estimated to constitute 75% of type B aortic dissection (TBAD) cases, with up to 50% of those progressing to become complicated. Despite this, and even though thoracic endovascular aortic repair (TEVAR) has proven its safety and effectiveness in the treatment on unTBAD, it is still being managed conservatively with optimal medical therapy (OMT). However, with the surge of emerging evidence in the literature supporting the use of pre-emptive TEVAR in unTBAD, the paradigm of clinical practice is shifting (1). Yet, there seems to be a strong debate on the optimal clinical, laboratory, morphological and radiological parameters defining the intervention threshold in clinical guidelines.
This review will discuss current literature pertaining to the risk factors in unTBAD patients undergoing TEVAR, with a focus on clinical, laboratory and morphological/radiographic features that increase the risk profiles of unTBAD patients. In the absence of clear clinical guidelines, a stratification scheme to identify and managed more vulnerable acute unTBAD patients with TEVAR is presented which could be executed using the risk factors identified in this review.
Clinical parameters
One of the most important clinical parameters to control in unTBAD is the heart rate, as when this exceeds 60 bpm in unTBAD patients it could lead to poorer long-term outcomes. Kodama et. al (2) observed lower rates of aortic events in OMT managed unTBAD patients with heart rate controlled at < 60 bpm (OR 0.25, p = 0.0059) (2). Surgical intervention was also lower at < 60 bpm versus > 60 bpm (0% versus 18.7%, P = 0.005) (2). The patient’s perception of pain also warrants caution. It is imperative to be vigilant of rarer absences of chest pain on admission, as this has been significantly associated with increased in-hospital mortality (OR 3.49, p = 0.01) (3). Even after OMT management, recurrent and/or refractory pain or refractory hypertension must be carefully observed. These parameters appear to elevate the risk of in-hospital mortality (17.4% versus 4%, p = 0.0003), and multivariate analysis showed are significant predictors of in-hospital mortality (OR 3.31, 95% CI 1.04 - 10.45, p = 0.041) (3).
Laboratory parameters
Certain blood tests are likely to have predictive and non-predictive values for aortic enlargement, and these will only be confirmed in studies that feature longer-term follow-ups. C-Reactive Protein (CRP) elevation is common in patients with TBAD and usually peaks between days 3-6 after the index event. Peak CRP, which needs to be obtained more than for reliable risk assessment (4), has been strongly linked to long-term adverse events in patients with unTBAD and could therefore be used as a prognostic marker. In a comparative study, a mean CRP levels of 12.0 mg/dL (with a lower limit of 9.61 mg/dL) and 19.5 mg/dL (with a lower limit of 14.90 mg/dL) were shown to be strong predictors of adverse events (HR 3.25, p = 0.01) (HR 6.02, p = 0.0001). This has been corroborated by others who demonstrate that CRP levels > 15.0 mg/dL may independently predict aortic events (OR 4.199, 95% CI 0.76 - 23.19, p = 0.1) (5). Peak CRP has been identified as a significant predictor of lower PaO2/FiO2 ratio which usually necessitates mechanical ventilation and is associated with further complications (6). However, as CRP is a non-specific marker, its utility in predicting the extent of aortic dissection may be limited by confounding inflammatory processes.
Fibrin degradation products (FDPs) may also be of prognostic value and appear to share a relationship with the patency and thrombotic status of the false lumen (FL) (7). The status of the FL is a known mortality determinant (8). Tsai et. al (8) previously found ± 3-year mean (± SD) mortality rates to be greatest in patients with partial FL thrombosis (31.6 ± 12.4 %) than those with patent (13.7 ± 7.1 %) or completely thrombosed FL (22.6 ± 22.6 %, p = 0.003). Nagaoka et. al (7) then found that FDP levels were significantly higher in patients with partial FL thrombosis (35.8 ± 43.2, median 18.8 μg/mL) versus those with patent or completely thrombosed FL (14.0 ± 21.3, median 5.5 μg/mL, p = 0.01). FDP may predict 1-year aortic events when admission levels are ≥ 20 μg/mL (OR 7.8, 95% CI 1.4 - 43.3), and can further assist radiological findings in the recognition of FL partial thrombosis (5, 7). Aortic enlargement, however, was not associated with platelet count, D-dimer, and thrombin-antithrombin III complex (5). The follow-up interval in this study (5) was only 1 year and therefore long-term significance remains elusive. FDP is also not easily measured in emergency settings and may therefore be less accessible for some institutions.
Troponin could be also used as a laboratory parameter in unTBAD by approximating the extent of ischaemic myocardial injury. Demand-ischaemia can occur due to blood pressure fluctuations, aortic regurgitation or an intimal flap covering the coronary ostia. Elevated troponin levels have been shown to be significantly associated with a higher risk for short-term mortality (OR 2.57, 95% CI 1.66 - 3.96) (9).
Morphological and radiologic parameters
Anatomic risk-stratification is currently the mainstay of TBAD assessment. Many morphological features have been noted that may lead to further aortic degeneration and secondary emergencies, including aortic morphology and diameter (10-14), position and size of entry tear (15, 16), and FL diameter and patency (12-14, 17, 18).
Aortic diameter
Aortic diameter has been reported as the most sensitive independent risk factor (HR 8.6, p < 0.01) for mortality in unTBAD (19). Strikingly, intervention rates at 1-, 5-, and 10- years in patients with an aortic diameter > 44mm were 18.8%, 29.5% and 50.3% versus 4.8%, 13.3% and 13.3% in those < 44mm (p < 0.01). Overall survival is illustrated in Figure 1 (19). Others have also described aortic diameter > 40 mm as predictor for late aortic events (HR 3.18, 95% CI 2.12 to 5.05, p < 0.001) (12) and > 40 mm is generally regarded as the cut-off for predicting late aortic intervention (15, 20).
The morphology of aortic diameter is also dictated by interplaying pressure relationships between the TL and FL. Clearly demarcated circular FL configurations are more highly pressurised due to their blood volumes. The fragility of the vessel wall in these “fusiform”- shaped aortas likely contributes to dilatation (12). Some have suggested that a circular FL may cause an elliptic TL configuration that has been associated with adverse aortic growth based on results from a conservatively managed cohort (n = 62) (21). Similarly, Song et. al (22) found increased FL: total aortic diameter ratios in the proximal and descending thoracic aortas of patients showing aortic growth during their follow-up. Radiology metrics have been proposed that could guide quantification. Marui et. al (12) suggested that a fusiform index of 0.64 could be an independent predictor of adverse aortic events. Briefly, the radiologic formula is defined as A / (B+C) where A is the maximum diameter of the proximal descending aorta, B is the diameter of the distal aortic arch, and C is the diameter of the descending aorta at the anatomical level of the main pulmonary artery.
It is likely that advancing MRI techniques will improve understanding of aortic diameter changes. Sailer et. al (23) devised the “FL circumferential extent” (FL-CE) metric which, unlike the conventional metrics of FL diameter and volumes, is unaffected by the position of the aortic dissection membrane. The FL-CE itself is defined as the angular distance between the two FL insertion points in the intimal flap - an angle more than 249° was found to be an independent predictor of adverse aortic events.