Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Meta-analysis

Eur J Vasc Endovasc Surg (xxxx) xxx, xxx

SYSTEMATIC REVIEW

Endovascular vs. Medical Management for Uncomplicated Acute and Subacute Type B Aortic Dissection: A Meta-analysis Martin Hossack a,*, Shaneel Patel a, Ivancarmine Gambardella b, Simon Neequaye a, George A. Antoniou Francesco Torella a

c,d

,

a

Liverpool Vascular and Endovascular Service, Royal Liverpool University Hospital, Prescott Street, Liverpool, UK Weill Cornell Medicine, New York Presbyterian Hospitals, New York, USA c Department of Vascular and Endovascular Surgery, The Royal Oldham Hospital, Pennine Acute Hospitals NHS Trust, Manchester, UK d Division of Cardiovascular Sciences, School of Medical Sciences, University of Manchester, Manchester, UK b

WHAT THIS PAPER ADDS This comprehensive and up to date meta-analysis demonstrates that there remains uncertainty whether thoracic endovascular aortic repair, in addition to best medical therapy, is beneficial in acute and subacute uncomplicated type B aortic dissection. Further research is required to understand which dissections would benefit from pre-emptive treatment.

Objectives: The aim was to compare peri-operative and late outcomes of patients with acute and subacute uncomplicated type B aortic dissection (uTBAD) treated by thoracic endovascular aortic repair (TEVAR) or best medical therapy (BMT). Methods: This was a Systematic review and meta-analysis of observational studies and randomised controlled trials (RCTs). The review was undertaken according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and registered with the International Prospective Register of Systematic Reviews (number: CRD42018094607). Multiple electronic databases were searched to identify relevant articles. The methodological quality of the included studies was assessed. The primary outcome measures were early mortality and re-intervention, late all cause and aorta related mortality, and re-intervention. Metaanalysis was used to produce pooled odds ratios (OR) or risk difference (RD) for peri-operative outcomes. Random effects models were applied. For late outcomes a time to event meta-analysis was conducted using the inverse variance model, reporting the results as hazard ratios (HR). Results: Eight original articles from six studies encompassing 14 706 patients (1 066 TEVARs) were eligible for inclusion. There were no statistically significant differences between TEVAR and BMT with regards to inpatient mortality (RD 0.01, 95% CI e0.01e0.02, p ¼ .46), early re-intervention by TEVAR (RD 0.02, 95% CI e0.01e 0.04, p ¼ .19) or surgery (RD 0.00, 95% CI e0.01e0.01, p ¼ 1.0). BMT was associated with a significantly lower risk of early stroke (OR 0.64, 95% CI 0.48e0.85, p ¼ .002), whereas the risk of late all cause (HR 1.54, 95% CI 1.27e1.86, p < .001) and aorta related mortality (HR 2.71, 95% CI 1.49e4.94, p ¼ .001) was significantly higher than with TEVAR. No suitable data regarding late aortic re-intervention was found for meta-analysis. Conclusion: Given the limited number and quality of suitable studies it remains uncertain whether TEVAR is beneficial in the management of acute/subacute uTBAD. Further research is required to understand which dissections would benefit from pre-emptive treatment. Keywords: Aorta, Aortic dissection, Endovascular procedures, Stents, TEVAR, Thoracic Article history: Received 27 August 2018, Accepted 2 August 2019, Available online XXX Crown Copyright Ó 2019 Published by Elsevier B.V. on behalf of European Society for Vascular Surgery. All rights reserved.

INTRODUCTION * Corresponding author. Liverpool Vascular and Endovascular Service, Department of Vascular Surgery, 8C link, Royal Liverpool University Hospital, Prescott Street, Liverpool L7 8XP, UK. E-mail address: [email protected] (Martin Hossack). 1078-5884/Crown Copyright Ó 2019 Published by Elsevier B.V. on behalf of European Society for Vascular Surgery. All rights reserved. https://doi.org/10.1016/j.ejvs.2019.08.003

Aortic dissection (AD) is a potentially life threatening condition. It can lead to compression of the true lumen, visceral malperfusion, and aortic rupture either in the acute phase, or later through aneurysmal degeneration of the false lumen.1 AD was originally classified by Daily et al.2 according to

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

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anatomical extent, with Type A dissections involving the ascending aorta, and Type B dissections limited to the aorta distal to the left subclavian artery. Type B dissections were historically managed medically with anti-impulse and antihypertensive therapy. However, with the advent of endovascular therapy and its successful implementation for the treatment of thoracic aortic disease,3e6 this changed. Type B aortic dissections (TBAD) complicated by ongoing pain, malperfusion, rupture or refractory hypertension should be managed by an emergency endovascular strategy, provided this is possible, in addition to strict blood pressure (BP) control.7 However, the management of uncomplicated Type B aortic dissection (uTBAD) is less clear cut. Data from observational studies has revealed that medical management leads to dismal long term outcomes, with a high proportion of aorta related interventions and mortality.8e10 Two randomised controlled trials (RCTs) have investigated the benefits of thoracic endovascular aortic repair (TEVAR) in the management of uTBAD. The ADSORB trial recruited patients with acute dissection (<14 days) but follow up at one year failed to demonstrate a significant clinical benefit.11 The Investigation of Stent Grafts in Patients with Type B Aortic Dissection (INSTEAD) trial recruited patients with subacute and chronic uTBAD, excluding patients who developed complications within the initial 14 days of dissection.The investigators found that over long term follow up of five years TEVAR significantly reduced aorta specific mortality compared with best medical therapy (BMT).12 Existing guidance from the European Society of Cardiology, based on data from the INSTEAD trial, states that TEVAR should be considered in uTBAD (class IIa, level B) but stops short of recommending it.1 Similarly, recent clinical practice guidelines from the European Society for Vascular Surgery (ESVS) state that TEVAR may be selectively considered in acute uTBAD (class IIb, level B), and should be considered in the subacute phase of chronic uTBAD (class IIa, level B) to prevent further aortic complications.13 Thus, although TEVAR has been shown to be feasible in patients with TBAD, the long term advantages over medical therapy in uncomplicated cases have yet to be unequivocally established. The aim was to systematically review the evidence in patients with acute or subacute uTBAD treated by either TEVAR and BMT or BMT alone, to see whether TEVAR improved early and late all cause and aorta related mortality. METHODS Objectives The questions being addressed in the systematic review were framed according to the PICOS (Participants, Interventions, Comparisons, Outcomes, Study design) component of Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA): Participants Patients (no age/sex limitation) with uTBAD of acute or subacute onset.

Martin Hossack et al.

Intervention TEVAR.

Comparison BMT.

Outcomes

1. Primary a. Early (in hospital or 30 day post-operative) mortality and re-intervention. b. Late all cause and aorta related mortality, and reintervention. 2. Secondary a. Complications (stroke, rupture, paraparesis, renal complications, aorta related adverse events). b. Radiological outcomes (false lumen thrombosis (FLT), aneurysmal degeneration).

Study protocol The methodology and objectives of this analysis were specified in a study protocol, which was registered with the number 42018094607 at the International Prospective Register of Systematic Reviews in Health and Social Care (PROSPERO), developed and maintained by the Centre for Reviews and Dissemination of the University of York, UK.14 The systematic literature review was undertaken according to the PRISMA guidelines.15 The review objectives were to investigate pre-operative characteristics, peri-operative (early) and post-operative (late) outcomes of patients undergoing TEVAR or BMT for uTBAD.

Eligibility criteria

1. Inclusion criteria: Only original RCTs and observational studies describing pre- and post-operative variables of patients undergoing TEVAR or BMT for uTBAD. There was no date limit on publications, and no age or sex limit on patients. 2. Clinical exclusion criteria: series not reporting on both TEVAR and BMT for uTBAD. Series reporting on only patients with chronic (>90 days) duration of uTBAD prior to TEVAR, and series reporting on fewer than 10 patients in either group were also excluded. 3. Non-clinical exclusion criteria: overlapping series (only the latest publication of serial reports of a certain cohort was included); non-original article (i.e. review, case report, editorial).

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

TEVAR vs. BMT for Uncomplicated Type B Aortic Dissection

Information sources Multiple electronic health databases (Medline, Embase, Cinahl, Cochrane Database of Systematic Reviews) were searched during the review period (4 September 2017 to 19 December 2018). The following trials databases were also searched for details of unpublished studies: World Health Organization International Clinical Trials Registry http://apps.who.int/trialsearch/, ClinicalTrials.gov http://clinicaltrials.gov/, ISRCTN Register http://www.isrctn.com/. A second level search was performed by manually interrogating the reference lists of the papers identified in the electronic search for suitable articles. Search strategy The databases were searched with an unrestricted search strategy, applying exploded Medical Subject Headings (MeSH) and keywords combined with the Boolean operators AND or OR to retrieve relevant reports: The following terms were used: “TEVAR”, “endovascular”, “stent”, “dissection”, “thoracoabdominal”, “abdominal”, “type B”, “descending”, “uncomplicated”, “asymptomatic”, “incidental”, “symptomless”, “painless”. For the full details of the explicit search strategy used for each database, please refer to the Supplementary material. Study selection Eligibility assessment was performed independently in an unblinded standardised manner by two reviewers (M.H. and S.P.).

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4. Demographic details: age, sex, comorbidities. 5. Primary outcome measures: early mortality and aortic re-intervention, late mortality, and aortic reintervention. 6. Secondary outcome measures: early or late morbidity (stroke, rupture, paraparesis, and renal complications), aorta related adverse events (defined according to individual study), and FLT.

Risk of bias assessment The methodological quality of observational cohort studies was assessed with the NewcastleeOttawa scale by two independent authors (M.H. and S.P.).16 Each study was judged on eight items, categorised into three groups: the selection of the study groups; the comparability of the groups; and the ascertainment of outcome of interest. For each item of the scale, the study was judged as low risk (1 star) or high risk (0 star) of bias up to a maximum of 9 stars. Studies scoring 9 stars were categorised as low risk, studies scoring 7 or 8, as moderate risk, and studies scoring 6 or less as high risk of bias. Similarly, the quality of randomised trials was assessed using the Cochrane Collaboration’s risk of bias tool.17 This covers six domains of bias: selection, performance, detection, attrition, reporting, and other bias. Using relevant trial characteristics, a judgement was formed for each item, as either high, low, or of unclear risk of material bias. These judgements were made independently by two authors (M.H. and S.P.), and consensus was reached through discussion when necessary.

Data collection process Data retrieved from the primary sources were entered into a spreadsheet, which was piloted with three randomly selected articles and refined accordingly. One author extracted the data from the included studies (M.H.) and a second author checked the extracted information (S.P.). Disagreements were resolved by discussion. Data were identified in published material only. Some authors did not report follow up data in a fashion suitable for statistical analysis. In some instances, the information was present but in a narrative form throughout the text, rather than extrapolated and explicitly stated in an alphanumeric fashion: in those cases, the necessary information was retrieved by methodically reading the text narrative so deriving the outcome of interest. Data items Extracted information was divided into six categories: 1. Publication details: first author, year and journal of publication. 2. Study details: study period, number of institutions, number of participants, controls and interventions, time to intervention from randomisation, inclusions, and exclusions. 3. Participants: Number of acute or subacute uTBAD.

Measures of treatment effect In hospital outcome data (e.g. those for in hospital mortality) were dichotomous; therefore pooled estimates were calculated using the odds ratio (OR) or risk difference (RD) and associated 95% confidence interval (CI). For late outcomes (e.g. all cause or aorta related mortality during follow up), a time to event data meta-analysis was conducted using the inverse variance model with the result reported as summary hazard ratio (HR) and associated 95% CI. A mixture of direct (e.g. from Cox regression models or from reported HRs with CI) or indirect methods (e.g. when p value from log rank test and total events were provided or from survival curves incorporating numbers at risk) were applied to calculate the individual study HR and standard error (SE) for specific outcome measures. Data extracted from published Kaplane Meier curves were digitalised using open source software Plot Digitizer (http://plotdigitizer.sourceforge.net). Unit of analysis The unit of analysis was the treated patient. Assessment of heterogeneity Interstudy heterogeneity was assessed visually using a forest plot. The I2 statistic was calculated to measure the

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

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Martin Hossack et al.

amount of interstudy heterogeneity. I2 values less than 50% were considered to be indicative of low heterogeneity, I2 values between 50% and 75% indicative of moderate heterogeneity, and I2 values greater than 75% indicative of significant heterogeneity. Assessment of reporting bias

For the meta-analysis of events rates Comprehensive MetaAnalysis (CMA) software was used (Biostat, Englewood, NJ, USA). Review Manager 5.3 software was used for data synthesis. RESULTS

A funnel plot to test for reporting bias was constructed if 10 or more studies were included for meta-analysis. Data synthesis The primary and secondary outcome endpoints in the entire review population were pooled by meta-analysing data from individual studies. The pooled proportion was calculated as the back transformation of the weighted mean of the transformed proportions. Random effects models were applied. A forest plot was created for each treatment effect. Sensitivity analysis The analyses were repeated removing one study at a time and observed for changes to the effect estimate.

Identification

Statistical software

Records identified through database searching n = 599

Study selection A total of 315 articles were retrieved according to the search strategy. The titles and abstracts were reviewed and 273 were excluded as not relevant or because they were conference abstracts only. Forty-two full text articles were retrieved and assessed. Four of these were excluded as they were not original studies (Fig. 1). A further 21 studies contained no comparison group (12 had no stented patients and nine had no medically treated patients). A further seven studies contained no data on the desired subgroup of patients (acute/subacute uTBAD). Of the remaining 10 articles, one study reported on fewer than 10 stented patients18 and so was excluded as per study protocol. One article was of an overlapping series. The Qin et al.19 study was excluded as a later study encompassing data from it

Additional records identified through other sources n=0

Screening

Records after duplicates removed n = 315

Records screened n =315

Eligibility

Records excluded (n =273) Full-text articles assessed for eligibility n = 42 Full-text articles excluded (n = 34)

Included

Studies included in qualitative synthesis n = 30

Not original study (n =4) No comparator group (n = 21) No data on acute or subacute uncomplicated TBAD subgroup (n = 7) <10 patients stented (n = 1) Overlapping series (n = 1)

Studies included in quantitative synthesis (meta-analysis) (n = 6)

Figure 1. Flowchart of literature search and article selection process of randomised controlled trials and observational studies describing outcomes of patients with acute and subacute uncomplicated type B aortic dissection (uTBAD) treated by thoracic endovascular aortic repair (TEVAR) or best medical therapy. TBAD ¼ type B aortic dissection; TEVAR ¼ thoracic endovascular aortic repair. Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

TEVAR vs. BMT for Uncomplicated Type B Aortic Dissection

was subsequently published and included in quantitative analysis. Three articles reported outcomes of the same cohort of patients at different time periods. Nienaber et al. (2010)20 and (2009)21 described the one and two year results of the INSTEAD trial, respectively. Data from these studies have been used in the quantitative analysis of early post-operative outcomes. A further analysis was subsequently conducted with longer (five year) follow up.12 The data from this article were used in the quantitative analysis of late post-operative outcomes. Thus, data for the INSTEAD study were taken from three articles for the purposes of this meta-analysis.

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Gore TAG device was used.11 Similarly, in Nienaber et al. the funding was from a Medtronic research group, several of the authors declared fees from Medtronic and a Medtronic device was used.12,20,21. Pre-operative characteristics Shah et al.24 did not report pre-operative characteristics of the included patients. All five of the other included studies reported pre-operative variables to a varying degree. Table 4 summarises the pre-operative characteristics of the patients in the included studies stratified by treatment received.

Study characteristics The characteristics of the individual studies11,12,20e25 have been summarised in Table 1. Of the six studies considered for qualitative and quantitative analysis, four were observational and two randomised controlled trials. The series were published between 2009 and 2016, reporting on patients with uTBAD from 1996 to 2014. The number of patients in each series ranged from 61 to 9 165, and the number of patients undergoing TEVAR in each series ranged from 11 to 504. Risk of bias within studies Assessment of the methodological quality of the included observational studies is summarised in Table 2. In both Shah’s24 and Trimarchi’s25 series the authors only reported early (inpatient) post-operative outcomes. These studies did not contribute to the quantitative analysis on late outcomes, but the length of follow up was considered adequate for early post-operative outcome analysis. Assessment of the methodological quality of the included RCTs is summarised in Table 3. Both RCTs were considered to be at high risk of bias in the “other bias” category. In Brunkwall et al. three of the trialists declared themselves as consultants for Gore, which funded the trial, in which a

Effects of interventions Table 5 displays the pooled event rates for the early outcomes in each group. Primary outcomes Early mortality. All studies reported early mortality (14 495 patients in total, with 1 066 TEVARs).11,12,20e25 The early mortality following BMT ranged from 0%11,12 to 10.3%,24 with an overall rate of 7.4%. The early mortality following TEVAR ranged from 0%11 to 8.5%,24 with an overall rate of 6.2%. The pooled results show no significant advantage of TEVAR for early mortality (RD 0.01, 95% CI e0.01e0.02, p ¼ .46). Statistical heterogeneity was low (p ¼ .35, I2 ¼ 10%) (Fig. 2a). Early (re)Intervention with TEVAR. Data on early endovascular intervention was available from three studies11,12,23 (535 patients, 285 TEVARs). The early endovascular intervention rate in the medical group ranged from 0%12 to 10%11 with an overall rate of 2.4%. The early endovascular re-intervention rate following TEVAR ranged from 0%11,23 to 2.9%,12 with an overall rate of 0.7%. The pooled results showed no significant difference between the early endovascular intervention rate following TEVAR with BMT over

Table 1. Details of included studies of systematic literature review and meta-analysis of outcomes of patients with acute and subacute uncomplicated type B aortic dissection (uTBAD) treated by thoracic endovascular aortic repair (TEVAR) or best medical therapy Author 11

Brunkwall Iannuzzi22 Qin23 Nienaber21 Nienaber20 Nienaber12 Shah24 Trimarchi25 Total

Year of publication

Journal

Study period

Institutions

Type of study

Participants

TEVARs

Onset

2014 2018 2016 2009 2010 2013 2014 2010 2009e2016

EJVES JVS JACC Circulation JTCVS Circulation: CI JVES Circulation e

2008e2010 2000e2010 2003e2014 2003e2005 e e 2009e2010 1996e2004 1996e2014

17 Statewide 3 7 e e Nationwide 24 e

RCT Observational Observational RCT e e Observational Observational e

61 9 165 338 140 e e 4 706 296 14 706

31 266 184 70

<14 d NR <14 d 14e365 e e NR <14 d e

504 11 1 066

CI ¼ Cardiovascular Interventions; d ¼ days; EJVES ¼ European Journal of Vascular and Endovascular Surgery; JVS ¼ Journal of Vascular Surgery; JACC ¼ Journal of the American College of Cardiology; JTCVS ¼ Journal of Thoracic and Cardiovascular Surgery; JVES ¼ Journal of Vascular and Endovascular Surgery; NR ¼ not reported; RCT ¼ randomised controlled trial.

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

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Martin Hossack et al.

Table 2. Methodological quality assessment with NewcastleeOttawa scoring system of observational studies describing outcomes of patients with acute and subacute uncomplicated type B aortic dissection (uTBAD) treated by thoracic endovascular aortic repair (TEVAR) or best medical therapy

Selection Representativeness of exposed cohort Selection of noneexposed cohort Ascertainment of exposure Demonstration outcome of interest not present at outset Comparability Comparability of cohorts by design or analysis

Outcome Assessment of outcome Was follow up long enough Adequacy of follow up Total

Trimarchi 201025

Shah 201424

Qin 201623

Iannuzzi 201822

*

*

*

*

*

*

*

*

* e

* e

* *

* e

- (No matching in design or adjustment in analysis)

* (stratified for age) * (adjusted for comorbidities)

- (No matching in design or adjustment in analysis)

* (risk adjusted in multivariable analysis)

* * e 5

* * e 7

* * * 7

* * e 6

* ¼ low risk of bias; - ¼ high risk of bias.

BMT alone (RD 0.02, 95% CI e0.01e0.04, p ¼ .19). Statistical heterogeneity was moderate (p ¼ .07, I2 ¼ 63%) (Fig. 2b). Early re-intervention with surgery. Data on early surgical intervention was available from three studies11,12,23 (535 patients, 285 TEVARs). The early surgical intervention rate in both the medical and TEVAR groups was 0% (Fig. 2c). Late all cause mortality. Time to event data were extracted from three articles12,22,23 (9457 patients, 520 TEVARs). One well designed RCT non-significantly favoured TEVAR12 but provided only 5% of the weight to the pooled results. Both

Table 3. Methodological quality assessment using The Cochrane Risk of bias tool of randomised controlled trials describing outcomes of patients with acute and subacute uncomplicated type B aortic dissection (uTBAD) treated by thoracic endovascular aortic repair (TEVAR) or best medical therapy Bias Selection bias Random sequence generation Allocation concealment Performance bias Blinding of participants and personnel Detection bias Blinding of outcome assessment Attrition bias Incomplete outcome data Reporting bias Other bias

Nienaber12 Brunkwall11 e e

þ þ

þ

þ

e

þ

e e þ

þ ? þ

e ¼ low risk of bias; þ ¼ high risk of bias; ? ¼ unclear risk of bias.

observational studies significantly favoured TEVAR. Metaanalysis showed that BMT was associated with a significantly higher risk of death than TEVAR with BMT (HR 1.54, 95% CI 1.27e1.86, p < .001). Eighty-three per cent of the weight of this result is from an observational study found to be at high risk of bias.22 Statistical heterogeneity was low (p ¼ .61, I2 ¼ 0%) (Fig. 3a). Late aorta related mortality. Time to event data were extracted from two articles (474 patients, 254 TEVARs), one observational study at moderate risk of bias,23 and one well designed RCT.12 Both studies significantly favoured TEVAR in reducing late aorta related mortality following uTBAD. Meta-analysis showed that BMT was associated with a significantly higher risk of aorta related mortality than TEVAR with BMT (HR 2.71, 95% CI 1.49e4.94, p ¼ .001). Statistical heterogeneity was low (p ¼ .89, I2 ¼ 0%) (Fig. 3b). Late re-intervention. The selected studies provided no data on this outcome suitable for meta-analysis. Secondary outcomes Early stroke. Data on early stroke rate were available from three of the included studies, all observational22e24 (14 027 patients, 954 TEVARs). The early stroke rate in the medical group ranged from 0%23 to 5.7%24 with an overall rate of 5.5%. The early stroke rate following TEVAR ranged from 0.5%23 to 8.3%,24 with an overall rate of 6.25%. All three studies favoured BMT, one significantly,24 with this study providing 69.3% weight for the pooled result. Overall there was a significant advantage of BMT over TEVAR with BMT (OR 0.64 95% CI 0.48e0.85, p ¼ .002). Statistical heterogeneity was low (p ¼ .91, I2 ¼ 0%) (Fig. 4a).

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

TEVAR vs. BMT for Uncomplicated Type B Aortic Dissection

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patients, 770 TEVARs). The event rate in the medical group ranged from 10.9%22 to 16.6%,24 with an overall rate of 12.7%. In the TEVAR group, the event rate ranged from 14.7%22 to 18.3%,24 with an overall rate of 17%. There was no significant difference between the treatment groups (OR 0.83, 95% CI 0.68e1.01, p ¼ .07). Statistical heterogeneity was low (p ¼ .29, I2 ¼ 10%) (Fig. 4d).

Table 4. Pre-operative characteristics of patients with acute and subacute uncomplicated type B aortic dissection (uTBAD) treated by thoracic endovascular aortic repair (TEVAR) or best medical therapy (BMT) Characteristics

BMT*

TEVAR*

Age e y Male sex e % Diabetes e % Hypertension e % Cardiac e % Respiratory e % Renal e % Smokers e % Patent false lumen e % Partial FLT e %

60.1e67 55e91.6 8.8e12.4 44.5e99 11e18 13.2 6.5 25e44.8 60.4e66.2 33.8e37

58.8e63.6 70e87.5 6.9e14.3 48.4e94 10.5e12 9.7 4.3 19.4e44 60.9e63.9 36.1e39.1

Late aorta related adverse events. Suitable time to event data were extracted from two articles12,23(474 patients, 254 TEVARs). The observational study by Qin et al.23 defined aorta related adverse events as aortic rupture, enlargement over 60 mm, retrograde type A aortic dissection, ulcer like projection, endoleak, or stent graft induced new entry (SINE). The RCT by Nienaber et al. defined them as crossover to TEVAR or conversion to open surgery, additional stenting or surgery required for rupture, malperfusion or aortic expansion, or enlarging aortic diameter of over 55 mm.14 Both studies favoured TEVAR, the observational study non-significantly,19 the RCT significantly.12 Metaanalysis showed a significant benefit of TEVAR in addition to BMT (HR 1.56, 95% CI 1.14e2.13, p ¼ .006). Statistical heterogeneity was low (p ¼ .49, I2 ¼ 0%) (Fig. 4e).

Data provided are the range of means. y ¼ years; BMT ¼ best medical therapy; TEVAR ¼ thoracic endovascular aortic repair; FLT ¼ false lumen thrombosis. * Mean or range of means.

Early rupture. Early rupture rate data were available from two of the included studies11,23 (399 patients, 215 TEVARs). The early rupture rate in the BMT group ranged from 0%11 to 1.9%23 with an overall rate of 1.6%. The early rupture rate following TEVAR was 0% in both studies.11,23 The pooled results show no significant advantage of TEVAR over BMT alone (RD 0.02, 95% CI e0.01e0.04, p ¼ .16). Statistical heterogeneity was low (p ¼ .57, I2 ¼ 0%) (Fig. 4b).

Radiological outcomes. No suitable time to event data were available on FLT or aneurysmal degeneration from the included studies for meta-analysis. Sensitivity analysis

Early paraparesis. Data on early paraparesis were available from two observational studies22,23 (9 321 patients, 450 TEVARs). The event rate in the medical group ranged from 0%23 to 2.9%22 with an overall rate of 2.8%. Following TEVAR, the rate of early paraparesis ranged from 0%23 to 3.4%,22 with an overall rate of 2%. There was no significant difference between the treatment groups (RD 0.00, 95% CI e0.02e0.01, p ¼ .65). Statistical heterogeneity was low (p ¼ .51, I2 ¼ 0%) (Fig. 4c).

All the analyses were repeated, removing one study at a time, to observe for changes in effect estimate for each outcome. Changes in the pooled effect estimates were found for the following outcomes. Early TEVAR. After removal of the study by Nienaber et al.12 the difference was significant in favour of TEVAR (RD 0.03, 95% CI 0.00e0.06, p ¼ .03; heterogeneity: p ¼ .14, I2 ¼ 55%).

Early renal complications. Data on early renal complications were available from two observational studies22,24 (13 689

Late all cause mortality. After removal of the studies by Qin et al.23 and Iannuzzi et al.22 (leaving only the study

Table 5. Pooled event rate for early outcomes in randomised controlled trials and observational studies describing outcomes of patients with acute and subacute uncomplicated type B aortic dissection (uTBAD) treated by thoracic endovascular aortic repair (TEVAR) or best medical therapy (BMT) Early outcome

BMT

TEVAR

Pooled estimate (95% CI)

Mortality Re-intervention with TEVAR Re-intervention with surgery Stroke Rupture Paraparesis Renal complications

0.05 0.03 0.01 0.04 0.02 0.02 0.14

(0.03e0.08) (0.01e0.13) (0.00e0.04)* (0.03e0.07) (0.01e0.05) (0.00e0.10) (0.09e0.20)

Heterogeneity p

I e%

.001 .06 .72 .001 .90 .12 .001

94 65 0 93 0 59 99

Pooled estimate (95% CI)

2

0.06 0.02 0.01 0.05 0.01 0.01 0.17

(0.03e0.09) (0.01e0.06) (0.01e0.03)* (0.03e0.11) (0.00e0.00)* (0.00e0.14) (0.14e0.21)

Heterogeneity p

I2 e %

.04 .32 .68 .01 .38 .08 .21

56 12 0 77 0 68 37

BMT ¼ best medical therapy; CI ¼ confidence interval; TEVAR ¼ thoracic endovascular aneurysm repair. * No events. Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

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A Study or Subgroup Trimarchi25 Nienaber12 Shah24 Brunkwall11 Qin23 Lannuzzi22

BMT alone Year Events

2010 2013 2014 2014 2016 2018

Total (95% CI)

TEVAR + BMT

Total

Events

Total

988 13429

66

1066

4 0 431 0 4 549

260 66 4202 30 154 8717

1 2 43 0 1 19

Heterogeneity: Chi2 = 5.56, df = 5 (p = .35); I2 = 10% Test for overall effect: Z = 0.74 (p = .46)

B Study or Subgroup Nienaber12 Brunkwall11 Qin23

BMT alone

11 70 504 31 184 266

–1

–0.5

0

Favours BMT alone

TEVAR + BMT

Risk Difference M–H, Fixed, 95% CI

Weight

0.01 [–0.01, 0.02]

100.0%

Risk Difference M–H, Fixed, 95% CI

Weight

–0.08 [–0.25, 0.10] –0.03 [–0.08, 0.02] 0.02 [–0.01, 0.04] 0.00 [–0.06, 0.06] 0.02 [–0.01, 0.05] –0.01 [–0.04, 0.02]

0.5

1.2% 4.0% 52.8% 1.8% 9.8% 30.3%

1

Favours TEVAR + BMT

Risk Difference M–H, Fixed, 95% CI

Year Events

Total

Events

Total

0 3 3

66 30 154

2 0 0

70 31 184

–0.03 [–0.08, 0.02] 0.10 [–0.02, 0.22] 0.02 [–0.01, 0.04]

25.5% 11.5% 63.0%

6

250

2

285

0.02 [–0.01, 0.04]

100.0%

Risk Difference M–H, Fixed, 95% CI

Weight

0.00 [–0.03, 0.03] 0.00 [–0.06, 0.06] 0.00 [–0.01, 0.01]

25.5% 11.5% 63.0%

0.00 [–0.01, 0.01]

100.0%

2013 2014 2016

Total (95% CI)

Heterogeneity: Chi2 = 5.38, df = 2 (p = .07); I2 = 63% Test for overall effect: Z = 1.32 (p = .19)

C

BMT alone

Study or Subgroup

Year Events

Nienaber12 Brunkwall11 Qin23

2013 2014 2016

Total (95% CI)

Risk Difference M–H, Fixed, 95% CI

Total

–1

–0.5 0 0.5 1 Favours BMT alone Favours TEVAR + BMT

TEVAR + BMT Events

Total

0 0 0

66 30 154

0 0 0

70 31 184

0

250

0

285

Heterogeneity: Chi2 = 0.00, df = 2 (p = 1.00); I2= 0% Test for overall effect: Z = 0.00 (p = 1.00)

Risk Difference M–H, Fixed, 95% CI

–1

–0.5 Favours BMT alone

0

0.5

1

Favours TEVAR + BMT

Figure 2. Forest plot of comparison of thoracic endovascular aortic repair (TEVAR) plus best medical therapy (BMT) vs. BMT alone for acute/ subacute uncomplicated type B aortic dissection (uTBAD). The solid squares denote the odds ratios or risk differences, the horizontal lines represent the 95% confidence intervals (CI), and the diamond denotes the pooled effect size. (A) Early all cause mortality. (B) Early endovascular intervention (medical) and re-intervention (TEVAR). (C) Early open surgical intervention. BMT ¼ best medical therapy; CI ¼ confidence interval; MH ¼ ManteleHaenszel test; TEVAR ¼ thoracic endovascular aortic repair; uTBAD ¼ uncomplicated type B aortic dissection.

Nienaber et al.12), the difference in favour of TEVAR became non-significant (HR 0.52, 95% CI 0.22e1.23, p ¼ .14). Aorta related adverse events. After removal of the study Nienaber et al.12 (leaving only Qin et al.23), the significant difference in favour of TEVAR was lost (HR 0.70, 95% CI 0.47e1.03, p ¼ .07). DISCUSSION Summary of evidence A comprehensive and up to date meta-analysis of studies comparing BMT alone to TEVAR with BMT for the treatment of acute and subacute uTBAD was conducted. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) methodology was used to rate the level of evidence for each outcome and the findings have been summarised in Table 6. This review indicates that TEVAR, when added to BMT, increases the early risk of stroke, but

not early mortality or re-intervention. TEVAR, however, appears to significantly reduce the risk of late all cause and aorta related mortality, as well as late aorta related adverse events. Regarding early all cause mortality, surgical intervention, and rupture, there is concordance among the studies, with none demonstrating a significant advantage for either treatment modality. For early endovascular re-intervention, results from individual studies appear contrasting. Counterintuitively, Nienaber et al.,12 who enrolled “stable” dissections older than 14 days, demonstrated a non-significant advantage of BMT whereas Brunkwall et al.,11 who enrolled only acute dissections within 14 days of symptom onset, and thought to be at higher risk of retrograde type A dissection, favoured TEVAR. Meta-analysis showed no statistical difference, even when the larger observational study by Qin et al.,23 in which the results are equivocal, was removed (as in the sensitivity analysis). It would seem any potential

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

TEVAR vs. BMT for Uncomplicated Type B Aortic Dissection

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A Study or Subgroup

Year

log[Hazard Ratio]

SE

Nienaber12 Qin23 Lannuzzi22

2013 2016 2018

0.654 0.643 0.386

0.439 0.284 0.108

Hazard Ratio IV, Fixed, 95% CI

Total (95% CI) Heterogeneity: Chi2 = 0.99, df = 2 (p = .61); I2 = 0% Test for Overall effect: Z = 4.37 (p < .0001)

.01

.1 Favours BMT alone

B Study or Subgroup

Year

log[Hazard Ratio]

SE

Nienaber12 Qin23

2013 2016

1.05 0.966

0.505 0.386

1

Hazard Ratio IV, Fixed, 95% CI

.01

.1 Favours BMT alone

1

Weight

1.92 [0.81, 4.55] 1.90 [1.09, 3.32] 1.47 [1.19, 1.82]

5.0% 12.0% 83.0%

1.54 [1.27, 1.86]

100.0%

Hazard Ratio IV, Fixed, 95% CI

Weight

2.86 [1.06, 7.69] 2.63 [1.23, 5.60]

36.9% 63.1%

2.71 [1.49, 4.94]

100.0%

10 100 Favours TEVAR + BMT

Total (95% CI) Heterogeneity: Chi2 = 0.02, df = 1 (p = .89); I2 = 0% Test for Overall effect: Z = 3.25 (p = .001)

Hazard Ratio IV, Fixed, 95% CI

10

100

Favours TEVAR + BMT

Figure 3. Forest plot of comparison of thoracic endovascular aortic repair (TEVAR) plus best medical therapy (BMT) vs. BMT alone for acute/ subacute uncomplicated type B aortic dissection (uTBAD). The solid squares denote the hazard ratios, the horizontal lines represent the 95% confidence intervals (CI), and the diamond denotes the pooled effect size. (A) Late all cause mortality. (B) Late aorta related mortality. BMT ¼ best medical therapy; CI ¼ confidence interval; MH ¼ ManteleHaenszel test; SE ¼ standard error; TEVAR ¼ thoracic endovascular aortic repair; uTBAD ¼ uncomplicated type B aortic dissection; IV ¼ inverse variance.

differences between the two modalities are likely to be clinically insignificant. For early stroke, two thirds of the weight of the pooled result came from a single observational study, which showed a significant advantage for BMT only.24 The other two studies, with lower weighting, also favoured BMT but non-significantly.22,23 For late outcomes, a meta-analysis of time to event data was performed to overcome heterogeneity in follow up duration between included studies. When the design and weighting of the included studies is taken in to account, it can be seen that 83% of the weight for the pooled result for late all cause mortality comes from an observational study judged to be at high risk of bias, whereas the well designed RCT by Nienaber et al.12 contributed only 5% weight to the pooled result. Removing the poorer designed studies, as in the current sensitivity analysis, changed the overall result from a significant to a non-significant advantage of TEVAR for late all cause mortality. The late aorta related mortality result is more definitive. Both Nienaber et al.12 and Qin et al.23 demonstrated a significant benefit of TEVAR when added to BMT, and were judged to be of low and moderate risk of bias respectively. The way in which TEVAR reduces late aorta related mortality is likely to be due to aortic remodelling. By inserting a stent graft scaffold into the true lumen, Nienaber et al. demonstrated a significant increase in true lumen diameter, reduction in false lumen diameter, and 90% complete FLT at five year follow up. Conversely in the BMT group, there was no significant true lumen increase or

false lumen shrinking. There was, however, a significant increase in aortic diameter and only a 22% complete FLT rate.12 Brunkwall et al. also demonstrated aortic remodelling with insertion of a stent graft, with a significantly larger maximum true lumen and smaller false lumen in the stented patients at one year follow up.11 This aortic remodelling did not translate into improved mortality, as none of the medically treated patients died. Thus, it would seem that the benefits of TEVAR, and therefore aortic remodelling, on mortality takes years to develop. As not all patients with uTBAD treated medically will die of aortic related causes, many need not be exposed to the increased early stroke risk associated with TEVAR. It would be convenient to select only patients for TEVAR who are at greatest risk of aneurysmal degeneration. Dake26 has produced a treatment algorithm for assessment of all TBAD, in which he uses six published predictors of late aortic events to classify an uTBAD as “high risk”. These are: (i) entry tear 10 mm,12,27 (ii) entry tear on the concavity of the distal aortic arch,28,29 (iii) maximum aortic diameter 40 mm,30e33 (iv) false lumen diameter 22 mm,34 (v) partial FLT,35,36 and (vi) a fusiform index of 0.64.37 Lavingia et al.38 retrospectively examined the CT scans of 117 patients presenting with uTBAD, of which 32 required delayed aortic intervention, and found that a true lumen volume/false lumen volume ratio of <0.8 was highly predictive for requiring intervention. At present, however, such prediction is not widely used in clinical practice. It may be tempting to observe the evolution of the aorta after the acute episode, in order to select patients whose aorta enlarges. The pitfalls to this approach are that

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

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Martin Hossack et al.

A

BMT alone

Study or Subgroup

Year Events

Total

Shah24 Qin23 Lannuzzi22

2014 2016 2018

Total (95% CI)

TEVAR + BMT

Brunkwall11 Qin23

2014 2016

0 3 3

31 184

0.00 [–0.06, 0.06] 0.02 [–0.01, 0.04]

184

0

215

0.02 [–0.01, 0.04]

Qin23 Lannuzzi22

2016 2018

0 250 250

–1

698 949

Weight 24.5% 75.5%

450

–0.00 [–0.02, 0.01]

0 9

8871

9

Risk Difference M–H, Fixed, 95% CI

–1

Events

Total

131

770

1647 12919

Odds Ratio M–H, Fixed, 95% CI

504 266

2

Heterogeneity: Chi = 1.11, df = 1 (p = .29); I = 10% Test for overall effect: Z = 1.82 (p = .07)

.01

E Study or Subgroup

Year log[Hazard Ratio]

SE

Nienaber12 Qin23

2013 2016

0.5978 0.3624

0.2763 0.198

Odds Ratio M–H, Fixed, 95% CI

Weight

0.83 [0.68, 1.01]

100.0%

0.89 [0.70, 1.13] 0.71 [0.50, 1.01]

Hazard Ratio IV, Fixed, 95% CI

Hazard Ratio IV, Fixed, 95% CI 1.82 [1.06, 3.12] 1.44 [0.97, 2.12] 1.56 [1.14, 2.13]

.01

67.0% 33.0%

.1 10 100 1 Favours BMT alone Favours TEVAR + BMT

Total (95% CI)

Heterogeneity: Chi2 = 0.48, df = 1 (p = .49); I2 = 0% Test for overall effect: Z = 2.75 (p = .006)

100.0%

–0.5 0 0.5 1 Favours BMT alone Favours TEVAR + BMT

TEVAR + BMT 92 39

1

0.00 [–0.01, 0.01] –0.01 [–0.03, 0.02]

154 8717

4202 8717

0.5

Favours TEVAR + BMT

184 266

Total

Total

0

100.0%

Risk Difference M–H, Fixed, 95% CI

Events

BMT alone

–0.5

Favours BMT alone

TEVAR + BMT

Heterogeneity: Chi2 = 0.44, df = 1 (p = .51); I2 = 0% Test for overall effect: Z = 0.45 (p = .65)

2

15.4% 84.6%

0 0

Total

Total (95% CI)

Weight

Risk Difference M–H, Fixed, 95% CI

30 154

BMT alone

2014 2018

Risk Difference M–H, Fixed, 95% CI

TEVAR + BMT

.1 1 10 100 Favours BMT alone Favours TEVAR + BMT

Total

Year Events

Shah24 Lannuzzi22

100.0%

Events

Study or Subgroup

Year Events

Odds Ratio M–H, Fixed, 95% CI

.01

Heterogeneity: Chi2 = 0.33, df = 1 (p = .57); I2 = 0% Test for overall effect: Z = 1.40 (p = .16)

Study or Subgroup

0.64 [0.48, 0.85]

59

Total

D

954

561 13073

BMT alone

Tota(95% CI)

69.3% 1.3% 29.3%

42 0 16

Year Events

C

0.66 [0.47, 0.93] 0.40 [0.02, 9.79] 0.60 [0.36, 1.01]

4202 154 8717

239 0 322

Study or Subgroup

Total (95% CI)

Weight

504 184 266

Total

Heterogeneity: Chi2 = 0.19, df = 2 (p = .91); I2 = 0% Test for overall effect: Z = 3.07 (p = .002)

B

Odds Ratio M–H, Fixed, 95% CI

Events

Weight 33.9% 66.1% 100.0%

.1 1 10 100 Favours BMT alone Favours TEVAR + BMT

Figure 4. Forest plot of comparison of thoracic endovascular aortic repair (TEVAR) plus best medical therapy (BMT) vs. BMT alone for acute/ subacute uncomplicated type B aortic dissection (uTBAD). The solid squares denote the odds ratios, risk differences, or hazard ratios, the horizontal lines represent the 95% confidence intervals (CI), and the diamond denotes the pooled effect size. (A) Early stroke. (B) Early rupture. (C) Early paraparesis. (D) Early renal complications. (E) Late aorta related adverse events. BMT ¼ best medical therapy; CI ¼ confidence interval; MH ¼ ManteleHaenszel test; SE ¼ standard error; TEVAR ¼ thoracic endovascular aortic repair; uTBAD ¼ uncomplicated type B aortic dissection.

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

TEVAR vs. BMT for Uncomplicated Type B Aortic Dissection

11

Table 6. Summary of findings for best medical therapy (BMT) compared with thoracic endovascular aortic repair (TEVAR) for acute or subacute uncomplicated type B aortic dissection (uTBAD) Outcomes

No. of participants (studies)

Certainty of Comments the evidence (GRADE)y

RD 0.01 (0.01e0.02)

14 495 (6 observational studies)

4 VERY LOW

HR 1.54 (1.27e1.86) (late all cause mortality) HR 2.71 (1.49e4.94) (late aorta related mortality) HR 1.56 (1.14e2.13) (late aorta related adverse events) OR 0.64 (0.48e0.85)

9 457 (3 non-randomised studies)

44 LOW

474 (2 non-randomised studies)

4444 HIGH

TEVAR results in a significant reduction in late aorta related mortality.

474 (2 non-randomised studies)

444 MODERATE

TEVAR is probably to reduce late aorta related adverse events

14 027 (3 observational studies)

4 VERY LOW

RD 0.02 (0.01e0.04)

535 (3 observational studies)

4 VERY LOW

BMT may reduce early stroke but we are very uncertain There is uncertainty about the difference in effect of BMT and TEVAR on early (re)intervention with TEVAR. It would appear that any difference in treatment effect is clinically insignificant. There is uncertainty about the effect of TEVAR on early aortic rupture There is uncertainty about the effect of TEVAR on early paraparesis There is uncertainty about the effect of TEVAR on early (re)intervention with surgery There is uncertainty about the effect of TEVAR on early renal complications

Anticipated absolute Relative effect effects* (95% CI) (95% CI) Risk Risk with with BMT TEVAR

Early mortality

62 per 1 000

1 per 1 000 (1e1)

Late all cause mortality

NA

Late aorta related mortality

NA

Late aorta related adverse events

NA

Early stroke

62 per 1 000

Early (re) intervention with TEVAR

7 per 1 000

40 per 1 000 (31e53) 0 per 1 000 (0e0)

Early aortic rupture

0 per 1 000

0 per 1 000 (0e0)

RD 0.02 (0.01e0.04)

399 (2 observational studies)

4 VERY LOW

Early paraparesis

20 per 1 000

0 per 1 000 (0e0)

RD 0.00 (0.02e0.01)

9 321 (2 observational studies)

4 VERY LOW

Early (re) intervention with surgery

0 per 1 000

0 per 1 000 (0e0)

RD 0.00 (0.01e0.01)

535 (3 observational studies)

4 VERY LOW

Early renal complications

170 per 145 per 1 000 1 000 (122 e172)

OR 0.83 (0.68e1.01)

13 689 (2 observational studies)

4 VERY LOW

There is uncertainty about the effect of TEVAR on early mortality TEVAR may reduce late all cause Mortality.

BMT ¼ best medical therapy; CI ¼ confidence interval; GRADE ¼ Grading of Recommendations Assessment, Development and Evaluation; HR ¼ hazard ratio; OR ¼ odds ratio; RD ¼ risk difference; TEVAR ¼ thoracic endovascular aortic repair; uTBAD ¼ uncomplicated type B aortic dissection. * The risk in the intervention group (and its 95% CI) is based on the assumed risk in the comparison group and the relative effect of the intervention (and its 95% CI). y GRADE Working Group grades of evidence: High certainty: There is full confidence that the true effect lies close to that of the estimate of the effect; Moderate certainty: There is moderate confident in the effect estimate: The true effect is probably close to the estimate of the effect, but there is a possibility that it is substantially different; Low certainty: There is limited confidence in the effect estimate: The true effect may be substantially different from the estimate of the effect; Very low certainty: There is very little confidence in the effect estimate: The true effect is probably substantially different from the estimate of effect.

once the aortic diameter reaches established thresholds for treatment, the dissection may no longer be in the more plastic acute/subacute phase, but into a chronic phase, characterised by a thickened immobile intimal flap. In this setting, TEVAR has been shown to be feasible but complete

aortic remodelling may occur only in a minority of cases.39 Thrumurthy et al.40 evaluated mid term outcomes from 17 studies encompassing 567 patients with chronic type B dissection and concluded that the absolute benefit of TEVAR over alternative treatment remained uncertain.

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

12

Limitations In this study the INSTEAD trial data were included as subacute uTBADs. Although there is no universally accepted definition of subacute AD, the European Society of Cardiology Task Force for the Diagnosis and Treatment of Aortic Disease defines it as presenting 15e90 days after onset, with chronic AD presenting after 90 days.1 The INSTEAD trialists included patients presenting with uTBAD 2e52 weeks after onset, although the median interval from dissection to TEVAR was 82 days. The chief importance of subdividing uTBAD according to onset is to help guide management based on the frequency of complications with conservative management, vs. the success with intervention. As a dissection becomes older, the aortic plasticity is thought to reduce such that remodelling of the aorta is less successful than in younger dissections. INSTEAD has shown that dissections up to one year old have a high rate of remodelling following TEVAR, justifying inclusion in this meta-analysis. Sensitivity analyses was performed with removal of INSTEAD trial data on all outcomes. This conferred a change in the effect estimates of two outcomes. For “Early TEVAR” the effect was to change a non-significant to a significant advantage of TEVAR over BMT. For “Aorta Related Adverse Events” the significant benefit of TEVAR was lost. The effect estimate for the rest of the outcomes remained unchanged. This meta-analysis is limited by the type and quality of included studies, which were largely observational and found to be of moderate23,24 or high risk of bias.22,25 Only two RCTs were suitable for inclusion,11,12 one of which was found to be at high risk of bias.11 Furthermore, the RCTs contributed a low proportion of the weighting for the pooled results, meaning that the observational studies had a larger effect on the overall outcomes. Of the four included observational studies,22e25 Ianuzzi et al.22 and Shah et al.24 used International Classification of Diseases, Ninth Revision (ICD 9) codes to identify patients for inclusion from the California Office Statewide Hospital Planning Development Database and National Inpatient Sample respectively. By using ICD 9 codes for “cardioplegia”, “valve repair”, and “operations on vessels of the heart”, they hoped to exclude Type A dissections. Furthermore, Ianuzzi et al.22 excluded complicated dissections by using ICD 9 codes for “bowel ischaemia”, “lower extremity ischaemia”, “acidosis and shock”, whereas Shah et al.24 excluded only “aortic rupture”. Thus, it is likely that dissections complicated by refractory pain and hypertension (Iannuzi) or with evidence of end organ ischaemia (Shah) were included erroneously. However, as these patients would have been managed with TEVAR rather than BMT, the actual TEVAR outcomes in truly uncomplicated patients may be better than those reported. Trimarchi et al.25 analysed data from patients enrolled in The International Registry of Acute Aortic Dissection (IRAD), a multinational, multicentre registry. Inherent limitations of multicentre registry data include different approaches to diagnosis and management and the potential for selection bias.

Martin Hossack et al.

Another weakness arises from the impossibility to determine the suitability for TEVAR of patients included in observational studies and treated by BMT only. It is possible that many of these patients might not have been suitable for endovascular treatment, thus patients treated by TEVAR may represent a subgroup with more favourable outcomes. The results of this systematic review cannot be considered conclusive. It would seem that a large, well designed randomised trial examining the late outcomes following TEVAR or BMT alone for uTBAD is still needed. This study does not address the issue of optimal timing for TEVAR following uTBAD. Studies focusing on uTBAD of acute/subacute presentation have been included, in the belief that both share a common plasticity of the intimal flap allowing remodelling. By including both acute and subacute uTBAD, the number of cases for meta-analysis has been increased. There is evidence that, in complicated patients, early TEVAR in the acute phase may result in a higher incidence of operative complications such as retrograde type A dissection,41 hence TEVAR is often delayed for at least two weeks in the acute setting whenever possible. In uncomplicated patients, this delay should be inconsequential, by definition. CONCLUSION Given the limited number and quality of suitable studies it remains uncertain whether TEVAR is beneficial in the treatment of acute/subacute uTBAD. Further research is required to understand which dissections would benefit from pre-emptive treatment. CONFLICT OF INTEREST None. FUNDING None. ACKNOWLEDGEMENTS The input and assistance of Beccy Roylance, University Hospital Aintree, with the literature search strategy is gratefully acknowledged. APPENDIX A. SUPPLEMENTARY DATA Supplementary data to this article can be found online at https://doi.org/10.1016/j.ejvs.2019.08.003. REFERENCES 1 Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H, et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J 2014;35: 2873e926. 2 Daily PO, Trueblood HW, Stinson EB, Wuerflein RD, Shumway NE. Management of acute aortic dissections. Ann Thorac Surg 1970;10:237e47.

Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003

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Please cite this article as: Hossack M et al., Endovascular vs. Medical Management for Uncomplicated Acute and Sub-acute Type B Aortic Dissection: A Metaanalysis, European Journal of Vascular and Endovascular Surgery, https://doi.org/10.1016/j.ejvs.2019.08.003