Clinical effectiveness

To our knowledge, this is the first assessment that considers the effectiveness and cost-effectiveness of CTA, CDU and CEU for surveillance after EVAR. The clinical evidence base for this assessment consists of two non-randomised comparative studies (with a total of 750 participants) and 25 observational cohort studies (with a total of 7196 participants), assessing various surveillance protocols after EVAR. The surveillance protocols were based on the use of either CDU and/or CEU in combination with CTA.

The majority of the included studies assessed EVAR surveillance protocols based on a combination of CDU and CTA. Three studies used CDU as the main imaging modality for surveillance after EVAR, two studies used CEU as the main imaging modality and one study used CEU in selected cases only. There were no studies that compared CDU surveillance with CEU surveillance.

The risk of bias was rated as being high or moderate for the majority of the included studies, with only three cohort studies rated as being at a low risk of bias according to the prespecified criteria for the risk-of-bias assessment (ReBIP checklist).^76,84,87

There was considerable heterogeneity among the included studies in terms of the surveillance protocols (imaging modality, frequency of imaging, duration of follow-up, reported outcomes, definition of clinical outcomes – for example, the definition of decreased aneurysm size, the axis of the diameter measured and the time points at which outcomes were assessed). Owing to the observed clinical heterogeneity, it was deemed to be inappropriate to perform a statistical synthesis of the reported outcomes.

We conducted a narrative synthesis of the main clinical findings and grouped studies according to their similarities in terms of modality and frequency of imaging. A combination of CTA and CDU was the most commonly implemented surveillance strategy. Studies that used a combination of CTA and CDU for surveillance after EVAR were published between 2001 and 2010. The second most common surveillance strategy involved CTA and/or CDU for early and mid-term assessments and CDU for long-term surveillance after EVAR. Studies assessing this type of strategy were published more recently, between 2009 and 2016.

This may indicate a growing trend towards a CDU-based surveillance. It is worth noting that one study that followed up 494 patients who underwent EVAR using CTA and CDU for early and mid-term imaging assessments and CDU for long-term surveillance reported the highest mortality and reintervention rates.⁹⁰ However, any comparisons between cohort studies are tentative, owing to the observed clinical heterogeneity. In this particular case, it is difficult to ascertain whether or not the reported high mortality and reintervention rates were observed because of the length of the follow-up period (12 years), the characteristics of the patient population or the imaging modalities used for surveillance.

Three of the included cohort studies were conducted in the UK.^41,78,82 Evidence from these studies was considered to be of moderate methodological quality, as the studies did not satisfy all of the criteria of the ReBIP checklist. One of these studies used CDU exclusively for surveillance after EVAR,⁷⁸ whereas the other two studies used a strategy based on a combination of CDU and CTA.^41,82 In particular, Harrison et al.,⁴¹ who followed up a total of 194 patients using a combination of CDU and CTA for early surveillance and CDU for long-term surveillance after EVAR, reported a mortality rate of 13% at 12 months. In contrast, a non-UK-based study that assessed 494 EVAR patients using a similar surveillance strategy reported 19.7% mortality during a median follow-up of 68 months.⁹⁰ In general, the proportion of patients requiring reintervention in the study by Harrison et al.⁴¹ was similar to that reported by other non-UK-based studies that used a combination of CTA and CDU for early surveillance and CDU for long-term surveillance. The study by Karthikesalingam et al.⁷⁸ used CDU at 1.5, 3, 5, 9, 12 and 18 months and annually thereafter to assess the role of peak systolic velocity provided by CDU for the prediction of limb complications in a cohort of 478 EVAR patients. The authors found that serial increases in the peak systolic velocity recorded during CDU surveillance were associated with an increased risk of stent–graft limb complications.⁷⁸

The proportion of patients with type I endoleaks identified by a surveillance strategy based on early and mid-term CTA and/or CDU and long-term CDU was comparable to that identified by a surveillance strategy based on a combination of CTA and CDU throughout the follow-up period (range 0–7.9% vs. 0.8–8.3%). No type III endoleaks were reported in the eight cohort studies that used early and mid-term CTA and/or CDU and long-term CDU for the surveillance after EVAR. It is worth noting that all but one study⁷⁶ were rated as being at a high or moderate risk of bias. The study by Freyrie et al.,⁷⁶ which was the only study that was rated as being at a low risk of bias in this surveillance category, reported two cases (1.1%) of type I endoleak, 23 cases (13%) of type II endoleak and no cases of type III or IV endoleak during a mean follow-up of 33 months.

Detection of limb occlusion was lower among cohort studies that used CDU for long-term surveillance after EVAR (range 0–1.1%) than cohort studies that used either CTA for long-term surveillance (range 3.1–3.7%) or a combination of CTA and CDU throughout surveillance (range 5.3–7.2%). This is, however, only an observation and not a causal association.

The study by Chaer et al.⁴⁰ evaluated the safety of long-term CDU for surveillance after EVAR. One hundred and eighty-four patients with shrinking or stable aneurysms who received CTA at 1 and 12 months after EVAR were followed up annually with CDU for up to 4 years. Freedom from endoleaks was 96% and freedom from secondary interventions was 95% at 4 years. The authors concluded that CDU-based surveillance after EVAR is safe in patients with stable aneurysms.

Similarly, the comparative study by Chisci et al.,⁶⁶ which compared CDU and CTA 1 month after EVAR and every 6 months afterwards (protocol I, 367 patients) with CDU and CTA 1 month after EVAR and CDU and radiography every 6 months afterwards (protocol II, 341 participants), reported no significant differences between the two surveillance strategies during the course of the study (3-year follow-up) in terms of reinterventions, clinical complications and mortality. The authors concluded that the current post-EVAR surveillance protocol could be simplified by adopting CDU as the main follow-up imaging modality and restricting the use of CTA to selective cases, when adverse events are suspected.

Cost-effectiveness

This assessment is the first model-based economic evaluation to consider the role of CDU, CEU and CTA for post-EVAR surveillance. Only the study by Bendick et al.¹³⁷ provided a head-to-head comparison of the three imaging modalities as first-line surveillance using data from a cohort of 40 individuals and considered both costs and clinical outcomes. All of the other economic evaluation studies identified in the systematic review compared the use of CTA as first-line monitoring with CDU only, with CTA being used after CDU for selected cases only, to provide further diagnostic information. Moreover, all of the studies assessed the reduction in costs as a result of the fewer number of CTA scans conducted in the ultrasound-based protocols. The model considered a broader measure of effectiveness based on a preference-based measure of utility in accordance with the UK economic evaluation methodological guidelines,⁶⁰ as well as a lifetime time horizon with all relevant consequences from the NHS perspective. None of the retrieved studies attempted an incremental analysis of the costs and clinical outcomes. For this reason, any comparison between the study’s results and those of the earlier economic evaluations should be conducted with caution.

The model results show that a surveillance strategy based on CDU as the imaging modality of choice becomes the strategy with the lowest expected costs, in addition to producing more QALYs than a strategy based exclusively on CTA. By comparison, although a surveillance strategy based exclusively on CEU would generate more QALYs, it would be more expensive, and the ICER would be well above the usual threshold used in the UK (i.e. £30,000). In addition, the base-case probabilistic analysis shows that a CDU-only strategy would have a probability of being cost-effective of between 57% and 64%, depending on the cost-effectiveness threshold (e.g. 62% at £30,000). Adding CTA to CDU or CEU in the first annual surveillance visit is not worthwhile, as it generates more QALYs but at a very high cost per QALY.

The base-case results, which show that CDU is the least expensive option, are in general agreement with those of previous economic evaluations that reported savings because fewer CTA tests were conducted in ultrasound-based protocols.^{41,45,66,137,138} However, although Bendick et al.¹³⁷ reported savings for a 3-year cost comparison between CEU- and CTA-based protocols, the model results indicate a higher expected cost for a CEU-only strategy than for a CTA-only strategy. This can be explained by the relatively lower specificity assumed for CEU in the economic model, which generates a higher proportion of false-positive results. These false-positive results will trigger further testing for a period of up to 2 years.

Extensive sensitivity analyses were conducted (see Appendix 15), with the base-case results being robust for the great majority of these. The sensitivity analysis showed that a CEU-only strategy could become cost-effective at very high rates of test sensitivity and specificity (e.g. when it was assumed to produce perfect information – sensitivity and specificity of 100% and no indeterminate results) and with a difference in the cost of CEU and CDU of < £55.

A further sensitivity analysis considered higher incidence rates for the abnormal Ib group (e.g. types I and III endoleaks and other abnormalities commonly detected by non-radiography imaging modalities). Annual incidence rates of 4% and above were used in this analysis. Compared with CDU-only surveillance, CEU-only surveillance becomes cost-effective, with an ICER of £29,756, when the annual incidence rate for this group is 7%. Although in clinical practice it is unlikely that an incidence rate of 7% for type I or type III endoleaks would be observed, an incidence rate of 6% for type II endoleaks with sac expansion is perhaps possible.

The interplay of sensitivity, specificity and unit costs of the test drives the results in the study’s model. For instance, a lower unit cost for CEU helps to make the CEU-based strategies relatively more cost-effective; however, cost on its own will not make a CEU-only strategy a cost-effective option. A higher specificity is also necessary in order to reduce the expected cost of the strategy as a result of the follow-up of individuals without an abnormality. In addition, a higher sensitivity triggers further interventions (e.g. secondary interventions for the abnormal Ia and Ib groups and further monitoring for the abnormal II group). As such, although these interventions might result in higher expected QALYs, they also add to the expected costs, with an uncertain final effect on cost-effectiveness.

The majority of patients in the cohort considered in the model will have no further need for subsequent interventions. Furthermore, in the base-case analysis, 70% of patients with an abnormality correspond to the abnormal II group. Because a large proportion of patients are elderly with multiple comorbidities, there are instances when a secondary intervention, which is considered to be technically indicated based on surveillance imaging, may not be carried out because the risk associated with the intervention is considered prohibitively high. Furthermore, in the cost–utility analysis, there is no benefit attributed to the reassurance that the abnormality is minor or from any information provided by the test. From the point of view of the economic model, following up individuals for whom no further interventions are possible just adds to the expected cost of the strategy, with no effects on QALYs. Future research should explore more broadly the effects of the information generated by the surveillance strategies and incorporate this within the economic analysis.

Clinical effectiveness

The clinical evidence identified for this assessment demonstrates that surveillance practice after EVAR is currently heterogeneous and the most effective method for surveillance has yet to be established.

Since the advent of EVAR, CTA has been the main imaging modality for long-term surveillance. A survey of current clinical practice after EVAR published by Uthoff et al.¹⁴⁷ in 2012, which involved 674 respondents from 52 countries worldwide, found that CTA was the imaging modality used most often for standard surveillance. A CTA scan at 1 year was scheduled by 64.5% of the respondents.

The use of CTA presents important drawbacks, including exposure to ionising radiation, which may result in an increased risk of cancer.³⁰ Moreover, the intravenous iodinated contrast medium used in CTA may damage renal function over time and increase the risk of contrast nephropathy. A study by Mitchell et al.,¹⁴⁸ published in 2010, found that the incidence of contrast-induced nephropathy was 11% among a cohort of 633 patients who received contrast-enhanced CT in the emergency department. Six patients with contrast-induced nephropathy developed severe renal failure and four (0.6%) died.¹⁴⁸ In most EVAR patients, these risks could be eliminated or reduced by modifying the surveillance protocol and limiting the number of CTA scans.^11,26,35,149

As the main purpose of surveillance is to identify complications and direct treatments, most surveillance protocols involve CTA scans at 1, 6 and 12 months and annually thereafter; however, some investigators have challenged the utility of the 6-month CTA in patients with a normal 1-month CTA.⁴⁶ The authors of the 5-year US Zenith multicentre trial have proposed a reduced surveillance protocol, with no 6-month CTA, for patients without early endoleaks.³⁶ According to the European Society for Vascular Surgery 2010 guideline,³¹ CTA and radiography should be used to categorise patients with and without endoleaks. Patients without an endoleak should be followed up with CTA at 12 months and with CDU and plain radiography thereafter, whereas those with a type II endoleak should receive CTA at 6 and 12 months and annual CTA and plain radiography thereafter.³¹ Similarly, the Society for Vascular Surgery practice guidelines recommend CTA at 1 and 12 months during the first year after EVAR. CTA at 6 months is added to the surveillance schedule only if the 1-month CTA identifies an endoleak or other abnormalities of concern.¹⁹ In the survey of current clinical practice after EVAR published by Uthoff et al.¹⁴⁷ in 2012, 48.6% of the 674 respondents agreed that, in the absence of an endoleak or AAA sac enlargement after initial CTA, no further CTA follow-up at 6 months is required.

Although the current trend is to reduce the frequency of CTA for early surveillance after EVAR or replace it with other imaging modalities, there is limited information on the optimal duration of long-term surveillance and if annual surveillance should continue indefinitely. A systematic review published by Nordon et al.²⁶ in 2010, assessed the rates of secondary interventions in 32 studies (17,987 EVAR patients) and reported the evidence in favour of a modified EVAR practice. The authors have observed a mean time to secondary intervention of approximately 1–1.5 years and have suggested that patients who have completed 3 years of surveillance without detection of endoleaks or sac enlargement can be discharged from standard surveillance.²⁶

Some investigators and clinical guidelines now recommend annual post-EVAR surveillance with CDU if the first annual CTA does not demonstrate an endoleak or residual sac enlargement.^12,19,73,150 Compared with CTA, CDU is less invasive, less expensive, easily available and less risky as it does not require the use of a contrast agent and does not expose the patient to repeated radiation. A number of studies and systematic reviews have confirmed the role of CDU in the evaluation of endoleaks.^{42,62,73,78,129,151–154} CDU can be regarded as a feasible and safer alternative to CTA, especially in patients with a stable aneurysm. Indeed, the number of centres using CDU seems to be increasing. In the survey by Uthoff et al.¹⁴⁷ published in 2012, the use of CDU during surveillance was reported by 36.3% of centres. High-volume, experienced centres were more likely to opt for CDU surveillance after 1 year than less experienced centres with fewer cases. Moreover, centres with a lot of EVAR experience were more likely to favour ultrasound for the follow-up of type II endoleaks.¹⁴⁷ Similarly, a UK telephone survey administered to 41 centres with 10 years’ experience in EVAR showed that 14 out of 41 (34.1%) centres used CDU as the primary surveillance modality.¹⁵⁵

In general, the evidence identified for this assessment showed no significant differences in terms of reinterventions and clinical complications between strategies based on the use of CDU for long-term surveillance after EVAR and those based on the use of CTA or CTA and CDU; however, the identified studies were clinically heterogeneous and any attempt to compare surveillance strategies should be considered to be tentative.

Current evidence on the use of CEU is limited, and CEU technology has evolved considerably over the past decade. A number of studies in the literature have reported a high accuracy of CEU in comparison with single and biphasic CTA.^57,156,157 A systematic review published in 2015,¹³⁰ which assessed the accuracy of CEU versus CTA for the detection of endoleaks during post-EVAR surveillance, concluded that, compared with CTA, CEU that utilises second-generation contrast agents is a highly sensitive modality for the detection of endoleaks and especially for the detection of type II endoleaks. Similarly, a study of 539 patients published by Millen et al.⁴³ in 2013, suggests that CEU may be useful for the resolution of clinical uncertainties that arise from conventional imaging modalities, especially in the classification of endoleaks.

There is growing evidence that the majority of reinterventions post EVAR are triggered by symptoms and are independent of standard surveillance.³⁹ Among the cohort studies included in this assessment, the proportion of patients requiring reintervention during surveillance ranged from 1.1% during a mean follow-up of 24 months⁴⁰ to 23.8% in a cohort of high-risk patients who presented with hostile neck anatomy after a mean follow-up of 32 months,⁸⁵ indicating that the risk of reintervention was not homogeneous and was related to patients’ characteristics. Karthikesalingam et al.,³⁹ who followed a cohort of 553 patients for a median follow-up period of 31 months (range 1–97 months) and assessed the extent to which surveillance after EVAR triggers reinterventions, found that 5.1% of asymptomatic patients underwent reintervention prompted exclusively by surveillance imaging, whereas 8.3% of patients presented symptomatically. Black et al.³⁷ assessed the number of secondary interventions after EVAR among 417 patients and reported that reinterventions were performed in 31 (7.4%), of whom only six (1.4% (6/417) had abnormalities that were detected by standard surveillance. Similarly, Dias et al.³⁸ found that the majority of follow-up CTA scans post EVAR did not lead to reintervention, and only 9.3% of asymptomatic patients (26/279) underwent a secondary procedure based on imaging findings detected by routine surveillance. The systematic review by Nordon et al.,²⁶ which assessed secondary interventions after EVAR from 32 papers and included a total of 17,987 cases, reported that surveillance practice alone initiated a secondary intervention in only 1.4–9% of cases.

It is possible that current surveillance practice is poorly targeted and that most patients do not benefit from an unstratified surveillance programme that does not take into account the individual risk of developing complications.¹¹ There is a growing interest in risk-stratified surveillance, whereby the frequency of imaging is directed by the preoperative risk of complications. Risk factors for early and late complications post EVAR have been documented.^158–160 Such an approach would allow more intense surveillance regimes to be targeted to those patients with greater risk, with less frequent surveillance in patients at low risk (Alan Karthikesalingham, St. George’s Vascular Institute, St. George’s University of London, 2016, personal communication).

Schanzer et al.¹⁶¹ assessed a large population of US Medicare beneficiaries (19,962 patients) who underwent EVAR between 2001 and 2008 and found that 50% of patients were lost to annual imaging follow-up by 5 years post EVAR. For the subset of patients with 8 years of follow-up, substantive declines in imaging follow-up continued, with only 37% undergoing an imaging study between year 6 and year 8.¹⁶¹ In the UK, Karthikesalingam and Holt,¹⁶² as part of the Multicentre Post-EVAR Surveillance Evaluation Study (EVAR-SCREEN), assessed 1539 patients who underwent EVAR in 10 EVAR-SCREEN collaborator centres. Five years after EVAR, 39.7% of patients remained compliant with the surveillance programme, whereas 21.4% were deliberately removed from surveillance. The authors reported that, compared with 131 compliant patients, non-compliant patients were more likely to undergo reintervention (5-year freedom from reintervention was 76.6% vs. 62.7% in compliant and non-compliant patients, respectively), but demonstrated similar all-cause mortality rates (5-year survival rate of 65.6% vs. 54.7% in compliant and non-compliant patients, respectively).¹⁶² These findings suggest that patients who undergo EVAR should receive appropriate information and counselling about the lifelong risk of complications and the need for annual imaging surveillance. UK centres that have adopted a comprehensive informative approach towards EVAR patients have reported satisfactory compliance rates (Professor Srinivasa Rao Vallabhaneni, 2016, personal communication). These findings also highlight that the current challenge facing EVAR surveillance is the frequency/timing of imaging, which currently is not targeted to patients’ risk of developing complications. It is possible that current imaging surveillance is performed too frequently for low-risk patients and not frequently enough for high-risk patients.

Cost-effectiveness

With regard to the reported economic model and cost-effectiveness analyses, there are a number of limitations that are worth mentioning. Both the identification and the selection of the input data were challenging. In order to identify the relative effect of different surveillance strategies, it was necessary to model a baseline situation (e.g. the cost and consequences of a situation without surveillance). Unfortunately, data to model the natural history of the disease were scarce. For this reason, the attention was turned to studies that analysed registry data. When particular input data were available from more than one source, the newest study was selected in an attempt to capture the technical developments of the modalities under consideration. Moreover, in the economic model, it was assumed that the imaging modalities differentiate the same conditions, that is, the tests identify a proportion of ‘abnormalities’ according to test sensitivity and specificity data. Once the overall abnormality proportion was defined, this proportion was divided among the abnormal Ia, Ib and II groups in the same proportions, regardless of the original test performed. In addition, the performance data used (i.e. sensitivity and specificity) were based on the detection of endoleaks (all types) that was reported by Karthikesalingam et al.¹³² Unfortunately, there were no sensitivity and specificity data available by type of abnormality and test, and therefore this is a limitation of the analysis.

A further assumption in the model is the perfect identification of certain abnormalities by plain radiography. In effect, all individuals developing a type Ia abnormality (e.g. non-endoleak needing elective intervention) are assumed to be correctly identified in the next surveillance visits through a plain radiography. Unfortunately, there were no data to inform the test performance for plain radiography in this context. Moreover, although plain radiography shows graft migration and kinking, the abnormal Ia group includes graft infection and limb thrombosis, which will not be seen on plain radiography. In fact, plain radiography in the model is always conducted alongside another imaging test. Therefore, the underlying assumption is that the conditions in the abnormal Ia group are perfectly identified by either plain radiography or the imaging test. A corollary of this is that the differences between the surveillance strategies are a result of the test performances for the abnormal Ib and II subgroups. This is in line with the project brief, as its main interest was related to the detection and management of endoleaks.

There are a number of structural assumptions in the study‘s model. First, no patients present with symptoms between surveillance visits. Individuals presenting with symptoms make surveillance less worthwhile. Hence, the assumption in the study’s model works in favour of surveillance. However, up to 8% of individuals could present with symptoms in a non-emergency situation (Professor Srinivasa Rao Vallabhaneni, 2016, personal communication), and the magnitude of the effect of this assumption on the model results is limited. Second, the model did not include a ‘do nothing’ alternative. Although this is recommended by a number of economic evaluation methodological guidelines,⁶⁰ a no-surveillance strategy was regarded as unacceptable and unrealistic for the UK context. Third, none of the strategies considered a partial use of CEU in a search for further information if the results from the CDU test were inconclusive. This is a limitation of the present analysis and material for further research. Fifth, all strategies considered surveillance on an annual basis. This was agreed with the clinical advisors, as annual surveillance frequency was deemed to be the only acceptable option. Finally, there was no risk stratification of the cohort. An alternative model could consider different surveillance strategies with differing visit frequencies, as well as alternative test arrangements, depending on the patient’s risk of developing complications.

The model might overestimate overall survival for this patient group compared with the results of the EVAR 1 trial (EVAR trial arm).⁴⁸ A higher overall survival rate would make any surveillance programme relatively more attractive, as people would enjoy the benefits for a longer period of time. The EVAR 1 trial includes individuals who are under surveillance. As a result, the lower mortality rate in the study’s model might correspond to events and conditions that cannot be avoided through a surveillance programme. Therefore, our model might overestimate the overall expected costs and QALYs because of a higher overall survival rate; the relative effect of this issue on the modelled strategies is ultimately unclear, although it is believed to be small in magnitude.

Suggested research priorities

• Further research is needed to assess the value of targeted surveillance (i.e. patients with a greater risk of complications may receive more frequent surveillance, whereas those with uncomplicated EVAR may undergo less frequent assessments or be discharged from surveillance). A large, multicentre trial with an extended follow-up period (over many years) would be required to answer the question of the optimal surveillance strategy after EVAR; therefore, the identification of high-risk EVAR patients mandating close follow-up may be a more realistic recommendation.
• If surveillance is to be targeted, is ultrasound-based surveillance (CDU and/or CEU) satisfactory for all patient groups, or are there groups for which CTA is required to avoid excessive risk?
• The criteria for identifying patients who are at a high risk of complications (e.g. use of validated score systems, risk prediction models) require further investigation.
• There is a need to clarify the role of plain radiography as part of EVAR surveillance. If CTA is to be performed less frequently or avoided, should plain radiography be mandatory or reserved for patients with abnormalities on ultrasound imaging?
• Future research should explore more broadly the effects of the information generated by the imaging modalities used for surveillance and incorporate this within the economic analyses.

Various aspects of EVAR surveillance may also warrant further consideration, for example it would be useful if:

• some indication of patients’ compliance with surveillance could be documented across centres in order to identify best surveillance practice and ensure that surveillance protocols are engaging with patients
• national clinical registries and databases could consider recording data on complications and mortality after EVAR according to the imaging modalities used for surveillance.