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Supplemental material for:

Optimising surveillance and re-intervention strategy following elective endovascular repair of abdominal aortic aneurysms

Lois G Kim, Michael J Sweeting, David Epstein, Maarit Vernermo, Fiona EV Rohlffs, Roger M Greenhalgh

Containing:

Supplementary Methods

Appendix 1 Parameter estimation

Appendix 2 Model implementation and internal validation

Supplementary Tables and Figures

Appendix Table 1 Summary of policies modelled

Appendix Table 2 Summary of patient characteristics in both EVAR trials and the HUH cohort Appendix Table 3 Hazard ratios for baseline variables and complication events on the risk of further complications, re-interventions and rupture in the EVAR-1 and EVAR-2 trials

Appendix Table 4 Hazard ratios for baseline variables and complication events on the risk of further complications, re-interventions and rupture in the HUH cohort

Appendix Table 5 30-day post-intervention probability of emergency re-intervention or death Appendix Table 6 Parameter estimates: costs and other inputs

Appendix Table 7 Details of AAA deaths observed in the EVAR trials and predicted from Model A (over 15-years, N=848, using rate parameters estimated from the EVAR trials)

Appendix Table 8 Rates of complications over time observed in the EVAR trials data

Appendix Figure 1 Convergence plots for models based on rates estimated from the EVAR trials Appendix Figure 2 Correspondence between the observed data (EVAR-1 and EVAR-2 trials; solid line) and the predicted number of events from Model A (run over 15 years for a combined-trial-like population, N=848, using EVAR-based rate parameters; dashed line). Mortality plots show Kaplan- Meier functions.

Appendix Figure 3 Unadjusted smoothed hazards for each complication type Supplementary Methods

Appendix 1 Parameter estimation

1.1 Modelling rates of complication following initial operation or an elective or emergency re- intervention

The times from an intervention (initial EVAR, elective re-intervention or emergency re-intervention) to each of the five complication categories were modelled separately using multiple failure-time models with time since last (re)-intervention as the time-scale, censoring for rupture and death. Rate estimation was carried out for complications following initial and re-interventions combined. Cause- specific hazards were estimated using a proportional hazards Weibull model with age at initial EVAR operation, sex, and other (non-corrected) complications included as predictors when these effects were statistically significant (p<0.05). For face validity, adjustment for previous complications was not included if it appeared to reduce the rate being estimated, since this is likely due to informative censoring. Complications were included in each of the five cause-specific transition models as time- dependent covariates and age was included as a linear effect. Robust standard errors were used to account for clustered data (multiple events per person). Complications occurring within the first 30 days following (re)-intervention are not included in this rate modelling. The vast majority of these complications will occur during the in-patient stay following the (re)-intervention; as such they are accounted for in the average procedure costs and outcomes applied for each (re)-intervention.

In the EVAR trials data, complications detected via CT that were not endoleak, migration, or kinking were excluded. Sac expansion events were identified retrospectively from the data using the current diameter and a previous diameter taken at least 6 months prior to the index event and classified into small expansion (>0mm/annum and <5mm/annum) or large expansion (≥5mm/annum) events.

Where multiple complications of the same category were recorded between re-interventions, only the first was used. Some re-intervention or rupture events were observed without a proceeding complication being formally recorded. This was perceived to be an issue with either missed detection of a complication or missing reporting on the case record form and to compensate we imputed a restricted cluster complication to occur at the mid-point between the last known negative scan and the rupture/re-intervention event.

Rates over time for each complication type are shown in Appendix Figure 2, with details in Appendix Table 8.

1.2 Modelling rates for re-interventions, ruptures and non-AAA mortality

multiple failure-time models with time from detection of a complication as the time scale. The rates of elective re-intervention were used in the DES model that investigated the EVAR observed re- intervention policy (Model B). Emergency intervention following rupture is modelled as a probability based on the observed data.

Time to rupture is modelled using Weibull rate modelling, using a time reset approach based on the occurrence of each complication following each (re)-intervention, with censoring for death. In Models A and B, time to elective re-intervention is also modelled in this way, based on the observed times to re-intervention, with censoring for death and rupture. Age, sex and other complication types were adjusted for where significant in the model (p<0.05) and the number of previous re- interventions was adjusted for as an a priori key factor for face validity of these models.

Mortality

All deaths within 30 days of an intervention were classified as AAA deaths, estimated using probability modelling, carried out separately for the initial elective intervention, elective re- intervention and emergency re-intervention. Deaths coded as AAA but occurring beyond this time without recorded rupture are referred to as “late AAA mortality” and are explicitly modelled as a post-30d rate. Individuals were considered at risk from late post-operative AAA mortality from both the post-operative survivor state and complication states.

Non-AAA mortality was modelled using a Gompertz distribution, stratified by sex. Age and an indicator for trial (EVAR-1 or EVAR- 2) were included in the model, since patients in EVAR-2 were known to have considerably more co-morbidity, with the effect of age also allowed to vary by trial (age x trial interaction).

1.3 Scan sensitivity and specificity

The sensitivity of US and CT was estimated by a systematic review². These authors assumed that CT is a perfect gold standard test for detecting endoleak. Although the specificity of US is not perfect, in practice it is very unlikely that re-intervention would be undertaken without thoroughly understanding the nature of the underlying complication, hence in practice the number of false positives leading to re-intervention can be assumed to be zero. It is assumed that CT and US can both measure aortic sac diameter to an acceptable degree of accuracy, though in practice there would be some measurement error³.

1.4 Empirical scan recall times

For Strategy A, observed scan times in the EVAR-1 and EVAR-2 data combined are used to inform the model. Draws are taken from the empirical distribution of next scan times, given the number of

previous scans. Due to data sparsity, the time of the 13^th scan and beyond is drawn from the observed distribution of time to 12^th scan.

Appendix 2 Model implementation and internal validation

2.1 Model convergence

Each policy model was run for 500,000 iterations and numbers of key events results scaled down accordingly (to EVAR trial cohort size for internal validation, or to 10,000 individuals for presentation of lifetime results). Convergence plots are provided in Appendix Figure 1. QALYs and costs were obtained from probabilistic sensitivity analysis run for 100,000 iterations. Mean discounted QALYS and mean discounted costs were stored for each strategy from each iteration, and the overall means of these presented alongside 2.5^th and 97.5^th centiles of the distributions.

2.2 Internal validation

Estimates of numbers of events in the observed EVAR-1 and EVAR-2 data combined are adjusted for censoring over the 15-year follow-up period for the purposes of model validation. Censoring due to loss to follow-up with respect to (i) complications (i.e. loss to scan follow-up), (ii) re-interventions (loss to hospital follow-up) and (iii) deaths (loss to Office of National Statistics (ONS) follow-up) may occur at different times for the same individual. The adjustment is made in 3-month increments using inverse probability of censoring weighting in order to appropriately inflate the number of observed events by the proportion censored⁴. Numbers of ruptures are not inflated as it is not clear when follow-up for this event was censored. Increases in numbers of events due to these adjustments are minimal as the majority of loss-to-follow-up occurs in the later part of follow-up, whereas the majority of events occur in the early years.

Mean costs in the observed data are estimated using the inflated events and unit costs. Estimation of mean life-years from the EVAR trial data is estimated using the Kaplan-Meier restricted mean at 15 years based on all-cause mortality, accounting for censoring.

Validation against modelled results

Observed and predicted numbers of key events validate well both in terms of total numbers of events and occurrence of these events over the 15-year trial follow-up period (Appendix Figure 2).

Supplementary tables and figures

Appendix Table 1 Summary of policies modelled

Strategy Surveillance policy Re-intervention policy

A As observed in the EVAR trials. All scans assumed to be via CT.

As observed in the EVAR trials, where decision to re- intervene following detection of a complication left to discretion of clinicians. Implemented using rate models for time to re-intervention following detection of each of the three complication types.

B As scheduled in the EVAR trials:

1m: CT scan 6m: CT scan 12m, and annually until death: CT scan

As observed in the EVAR trials (see Strategy A)

C As scheduled in the EVAR trials (see Strategy B) As described in ESVS 2011 guidelines:

Elective re-intervention if restricted cluster or sac growth (≥10mm increase from pre-op baseline) detected No elective re-intervention otherwise.

D As described in ESVS 2011 guidelines:

1m: CT scan 6m: CT for those with any complication detected at 1m or previous re-intervention 12m, and annually until death: CT scan for those with any complication detected at any previous scan since last (re)-intervention/ US scan otherwise, plus immediate CT for those with US-detected restricted cluster complications

As described in ESVS 2011 guidelines (see Strategy C)

E No long-term follow-up:

1m: CT scan and outpatient visit 12m, and annually to 5y: US scan and outpatient visit

As described in ESVS 2011 guidelines (see Strategy C)

After 5y: No further follow-up Additionally assume restricted cluster and sac growth detected by US is checked with an immediate CT scan.

F 3m: CT scan

12m and annually thereafter: Handheld US, with CT (plus MRA if needed) if sac expansion >0mm/year detected by US.

Elective re-intervention if restricted cluster complication OR type II endoleak with sac growth >5mm/annum detected at CT scan

Appendix Table 2 Summary of patient characteristics in both EVAR trials and the HUH cohort

EVAR-1 EVAR-2 EVAR-1 & EVAR-2

combined HUH, Finland

N 623 225 848 391

Age at initial EVAR intervention (mean (SD), years)

74.2 (6.1) 77.1 (6.7) 75.0 (6.4) 74.6 (8.0)

Female (n (%)) 62 (10.0%) 28 (12.4%) 90 (10.6%) 48 (12.3%)

AAA diameter at initial EVAR intervention (mean (SD, mm)

6.4 (0.9) 6.8 (1.0) 6.5 (0.9) 6.3 (0.9) Body mass index (Kg/m²) ⁽¹⁾ 26.6 (4.6) 26.6 (4.8) 26.6 (4.6) 27.3 (5.3)

Diabetes ⁽²⁾ 58 (9.3%) 37 (16.5%) 95 (11.2%) 78 (20.0%)

Smoking status ⁽³⁾

Current 130 (20.9% 38 (16.9%) 168 (19.8%) 98 (25.1%)

Ex/Never 492 (79.1% 187 (83.1%) 679 (80.2%) 292 (74.9%)

1 Body mass index missing in 1 patient from EVAR-1, 1 patient from EVAR-2 and 1 patient from HUH

2 Diabetes status missing in 2 patients from EVAR-1, 1 patient from EVAR-2 and 1 patient from HUH

3 Smoking status missing in 1 patient from EVAR-1 and 1 patient from HUH

Appendix Table 3 Hazard ratios for baseline variables and complication events on the risk of further complications, re-intervention and rupture in the EVAR-1 and EVAR-2 trials

From state To state Hazard ratios (95% CI)

Development of complications

(Re)-intervention

Restricted cluster complication, >30d⁽¹⁾

Large sac growth 1.62 (1.05, 2.51) Small sac growth 1.59 (1.09, 2.32) Type II endoleak, >30d⁽²⁾ Age 1.04 (1.02, 1.06) Restricted cluster 1.67 (1.01, 2.77) Large sac growth, >30d⁽³⁾ Age 1.04 (1.02, 1.06) Small sac growth, >30d⁽⁴⁾ -

10mm change from baseline, >30d⁽⁵⁾

Age 1.07 (1.04, 1.11)

Large sac growth 4.42 (2.79, 6.99) Small sac growth 1.65 (1.05, 2.59) Occurrence of elective re-intervention

Restricted cluster⁽⁶⁾

Elective re-intervention

Large sac growth 1.86 (1.22, 2.85) Previous

re-intervention

1.89 (1.25, 2.88)

Type II endoleak⁽⁷⁾ Restricted cluster 2.54 (1.33, 4.85)

Large sac growth 3.07 (1.76, 5.34) Previous

re-intervention

1.37 (0.54, 3.48)

Large growth⁽⁸⁾ Restricted cluster 6.01 (3.33, 10.8)

Type II endoleak 2.00 (1.04, 3.85) Previous

re-intervention

1.78 (0.93, 3.42) 10mm change

from baseline⁽⁹⁾

Restricted cluster 2.60 (1.20 5.62) Large sac growth 2.70 (1.17, 6.26) Previous

re-intervention

1.75 (0.83, 3.67) Rupture

Any complication Rupture⁽¹⁰⁾ Female 2.56 (1.22, 5.38)

Restricted cluster and/or large sac growth

62.7 (8.5, 462.0)

Notes:

Robust SEs for clustered data by patient; includes only effects at p<0.05, except models for re-intervention, which all include a binary indicator for previous re-intervention; age reflects age at initial EVAR intervention

PSA distribution: Parameters are sampled from

^

β ,V

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β

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N¿ ^where β is the vector of log hazard ratios for the transition followed by the log scale and log shape parameters of the Weibull proportional hazards model.

(1) Weibull PH model with baseline scale=0.07 (SE=0.008) and shape=0.52 (SE=0.05) (age is centred at age 75).

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0.486, 0.463,−2.619,−0.641

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−0.0003 − 0.0004 0.0122

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^

β=(0.038, 0.515,−2.219,−

0.882 )

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0.0002

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^β=

(

0.041,−2.780,−0.248

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−0.0001 0.0075 0.0001

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^

β=(−2.574, 0.124,1.132)

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(

0.070, 1.486,0.496,−2.966,−0.949

)

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( ^{−0.0004 −0.0002 −0.0004 0.0003 0.0003 −0.0030 −0.0056 −0.0042 0.0549 −0.0061 −0.0083 0.0533 −0.0020 0.0154 0.0059} )

(6) Weibull PH model with baseline scale=0.35 (SE=0.05) and shape=0.40 (SE=0.02) (age centred at age 75)

^

β=(0.623, 0.640,−1.045,−

0.905 )

0.0467

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−0.0152 − 0.0161 0.0182

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0.0007 0.0013 0.0007

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)=( 0.0031

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^β=

(

1.121, 0.931,0.311,−2.450,−0.586

)

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V

( ^

β)=

( ^{−0.0139 −0.0234 −0.0229 0.0800 0.0012 −0.0122 −0.0081 0.1094 0.0145 −0.0317 0.2282 0.0151 −0.0117 0.0404 0.0129} )

(8) Weibull PH model with baseline scale=0.07 (SE=0.02) and shape=0.62 (SE=0.05) (age centred at age 75)

^

β=(1.793, 0.693,0.577,

−2.707,−0.474 )

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( ^

β)=

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(9) Weibull PH model with baseline scale=0.06 (SE=0.02) and shape=0.47 (SE=0.06) (age centred at age 75)

^β=

(

0.955, 0.994,0.558,−2.823,−0.756

)

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V

( ^

β)=

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(10) Weibull PH model with baseline scale=-7.12 (SE=1.03) and shape=0.60 (SE=0.09) (age centred at age 75)

^

β=(0.939, 4.138,−7.116,−0.514

)

0.1437

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Appendix Table 4 Hazard ratios for baseline variables and complication events on the risk of further complications, re-intervention and rupture in the HUH cohort

From state To state Hazard ratios (95% CI)

Development of complications

(Re)-intervention

Restricted cluster

complication, >30d⁽¹⁾

Large sac growth 2.57 (0.64, 10.3) Small sac growth 1.46 (0.37, 6.36) Type II endoleak, >30d⁽²⁾ Age 1.02 (1.00, 1.05)

Restricted cluster -

Large sac growth, >30d⁽³⁾ Age 1.05 (1.01, 1.09)

Small sac growth, >30d⁽⁴⁾ - -

10mm change from baseline,

>30d

Age

As EVAR-based model Large sac growth

Small sac growth Occurrence of elective re-intervention

Restricted cluster⁽⁵⁾

Elective re-intervention

Large sac growth 1.23 (0.52, 2.92) Previous

re-intervention

2.24 (1.03, 4.88)

Type II endoleak⁽⁶⁾ Restricted cluster 2.34 (0.69, 7.91)

Large sac growth 5.68 (2.61, 12.4) Previous

re-intervention

1.21 (0.58, 2.53)

Large sac growth⁽⁷⁾ Restricted cluster -

Type II endoleak 1.30 (0.48, 3.56) Previous

re-intervention - Rupture

Any complication Rupture⁽⁸⁾ Female 0.67 (0.09, 4.96)

Restricted cluster and/or large sac growth

4.54 (1.21, 17.07)

Notes:

Variables from EVAR-based modelling retained in Helsinki-based rate models, except where the variable is estimated to reduce the rate of rupture.

Rate of ≥10mm change from baseline estimated from EVAR trials since not recorded in Helsinki data.

Re-interventions from this complication are not modelled. There are no AAA coded deaths without rupture

>30d after intervention in the Helsinki data. Non-AAA mortality is estimated from the EVAR trials in order to model contemporary surgery in an EVAR-1-like population.

Robust SEs for clustered data by patient; includes only effects at p<0.05, except models for re-intervention, which all include a binary indicator for previous re-intervention; age reflects age at initial EVAR intervention

PSA distribution: Parameters are sampled from

^

β ,

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V

( ^

β

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N¿ ^{where β} is the vector of log hazard ratios for the transition followed by the log scale and log shape parameters of the Weibull proportional hazards model.

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β=(0.942, 0.380,−2.526,−

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)

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β=(−0.395, 1.514,−3.977,−1.057

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Appendix Table 5 30-day post-intervention probability of emergency re-intervention or death

From state To state Probability Distribution for PSA

^

β V

( ^

β) EVAR Trials-based estimates

Rupture Emergency re-intervention 0.28 -0.969 0.1254

Initial intervention 30d all-cause mortality (AAA death) 0.026 -3.626 0.0467

Elective re-

intervention

30d all-cause mortality (AAA death) 0.017 -4.066 0.3390

Emergency re-

intervention

30d all-cause mortality (AAA death) 0.27 -1.012 0.3409 Helsinki-based estimates

Rupture Emergency re-intervention 0.50 0 0.5

Initial intervention 30d all-cause mortality (AAA death) 0.0026 -5.966 1.0026

Elective re-

intervention

30d all-cause mortality (AAA death) 0.0089 -4.718 1.0089

Emergency re-

intervention

30d all-cause mortality (AAA death) 0.43 -0.288 0.5833 Note: The probabilities of complication in the first 30d following endovascular intervention were assumed the same for initial aneurysm repair, elective re-intervention or emergency re-intervention

PSA distribution: Parameters are sampled from

^

β ,

^

V

( ^

β

)

N¿ ^where β is the logit of the probability for the transition.

Appendix Table 6 Parameter estimates: costs and other inputs

Parameter Value Source

Cost of re-intervention £8782 NHS reference costs 2015-16⁵

Cost of emergency re-intervention £17258 IMPROVE⁶

Cost of CT scan (in hospital) £104 NHS reference costs 2015-16⁵ Cost of US scan (in hospital) £58 NHS reference costs 2015-16⁵

Cost of outpatient visit £140 NHS reference costs 2015-16⁵. It is assumed that all US and CT scans also require an outpatient visit Cost of portable US (in primary

care)

£58 NHS reference costs 2015-16⁵. Assumed that no outpatient visit is required

Utility multiplier after elective re- intervention

0-3m: 0.964 3-12m: 0.982

The EVAR-1 trial found that at 3m after EVAR, the utility loss is 3.6% of baseline value (EVAR-1) At 12m, patients recover to baseline value. It is assumed linear recovery from 3m to 12m⁷.

Utility multiplier after emergency re-intervention

Linear recovery over 1 year from 0 to 1.

Assumption Sensitivity of in-hospital US to

detect endoleak

0.82 Abraha et al 2017²

Sensitivity of portable primary care US to detect endoleak

0.00 By assumption

Sensitivity of CT to detect endoleak 1.00 Abraha et al 2017² Sensitivity of in-hospital and

portable US to detect sac growth

1.00 By assumption

Sensitivity of CT to detect sac growth

1.00 By assumption

Specificity of CT and US 1 It is assumed that all suspected complications will be fully investigated and confirmed before re-intervention

Appendix Table 7 Details of AAA deaths observed in the EVAR trials and predicted from Model A (over 15-years, N=848, using rate parameters estimated from the EVAR trials)

EVAR-1 / EVAR-2 observed

Model A

Total number of AAA deaths 73 70.7

In first 30 days following initial EVAR intervention 22 21.5 In first 30 days following elective re-intervention 3 2.6 In first 30 days following emergency re-intervention 4 2.8 Post-rupture (without emergency re-intervention) 29 32.6

>30 days following an intervention

(without rupture, but AAA-coded death) 11 11.2

Appendix Table 8 Rates of complications over time observed in the EVAR trials data

Rate per py (number of events) EVAR Trials

0 – 1m 1 – 3m 3-6m 6m+

Restricted cluster complications^a 0.52 (42) 0.16 (26) 0.06 (13) 0.03 (147)

Endoleak type II^b 0.27 (22) 0.34 (53) 0.13 (29) 0.03 (135)

0-1m 1m – 12m 12m-24m 24m+

Small sac expansion^c NA 0.05 (42) 0.11 (73) 0.11 (215)

Large sac expansion^d NA 0.05 (45) 0.06 (48) 0.03 (113)

Change from pre-op sac expansion^e NA 0.06 (52) 0.02 (13) 0.01 (52) HUH

0 – 1m 1 – 3m 3-6m 6m+

Restricted cluster complications 0.40 (16) 0.24 (19) 0.06 (6) 0.03 (39)

Endoleak type II 0.40 (16) 0.71 (53) 0.52 (46) 0.05 (60)

0-1m 1m – 12m 12m-24m 24m+

Small sac expansion NA 0.03 (11) 0.05 (16) 0.04 (29)

Large sac expansion NA 0.03 (10) 0.05 (18) 0.04 (33)

a. Restricted cluster complication: a composite outcome comprising any of: kinking, migration, endoleak type I, endoleak type III

b. With or without other complication c. ≥5mm / year

d. ≥0mm / year and <5mm/year e. ≥10mm since baseline f.

Appendix Figure 1 Convergence plots for models based on rates estimated from the EVAR trials

Appendix Figure 2 Correspondence between the observed data (EVAR-1 and EVAR-2 trials; solid line) and the predicted number of events from Model A (run over 15 years for a combined-trial-like population, N=848, using EVAR-based rate parameters; dashed line). Mortality plots show Kaplan-Meier functions.

(a) Restricted cluster complications

(b) Type II endoleaks

(c) Small sac growths

(d) Large sac growths

(e) Change from pre-operative baseline sac growths

(f) Elective re-interventions

(g) Ruptures

(h) AAA mortality

(i) All-cause mortality

Appendix Figure 3 Unadjusted smoothed hazards for each complication type

(a) Restricted cluster events

(b) Endoleak type II events

(c) Small annual sac expansion events

(d) Large annual sac expansion events

(e)

(f) Change from pre-op baseline sac expansion events

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