Web Supplement

Web Supplement

Endovascular repair of abdominal aortic aneurysm in patients physically ineligible for

open repair: very long-term follow-up in the EVAR 2 randomised controlled trial

Contents

Trial Investigators Page 3

Methods for per protocol and causal analyses Page 4

Supplementary information on defining re-interventions and censoring criteria Page 4 Table S1: Baseline characteristics of patients in the EVAR trial 2 Page 5 Table S2: Causes of death by period since randomisation Page 6 Table S3: Hazard ratios comparing EVAR vs. no intervention for three Page 7 pre-specified subgroups and three exploratory subgroups

Table S4: Comparison of trial results based on intention-to-treat, per-protocol Page 8 and causal analyses

Table S5: Re-intervention according to time since randomisation Page 9 Table S6: All reinterventions from any relevant procedure according to Page 10 time since randomisation

References Page 11

Trial Investigators

Grant Applicants: R.M. Greenhalgh (principal investigator), J.T. Powell, M.J. Sweeting, M. Sculpher, D. Epstein, C. D.

Bicknell.

Trial Management Committee: R.M. Greenhalgh MD (chair), J. T. Powell MD, M.J. Sweeting PhD, D. Epstein PhD, C.D.

Bicknell MD, R. Von-Allmen MD, T. R. Wyss MD, N. Burfitt FRCR

Trial Steering Committee: R.J. Lilford (chair), R.M. Greenhalgh, M. Wyatt, S.G. Thompson, M. Sculpher.

Data Monitoring and Ethics Committee: G. Fowkes (chair), R. Morgan, B. Campbell.

End-Points Committee: J.T. Powell (chair), A. Halliday, S. Gibbs.

Data and Trial Management: R. Patel (trial manager), M. Kaderbhai (data manager).

Trial Manager (1999 to 2010): L.C. Brown Statistical Analyses: M.J. Sweeting

Regional Trial Investigators Committee (numbers in parentheses indicate the number of patients entered into both the EVAR 1 and EVAR 2 trials): K. Varty, C. Cousins, Addenbrookes Hospital, Cambridge (10); D. Harkin, R.J. Hannon, L.

Johnston, Belfast City Hospital, Belfast (53); A.W. Bradbury, M.J. Henderson, Birmingham Heartlands Hospital, Birmingham (8); D. Ritoo, S.D. Parvin, D.F.C. Shepherd, Bournemouth General Hospital, Bournemouth (68); C.

Bicknell, R.M. Greenhalgh, A.W. Mitchell, Charing Cross Hospital, London (27); S. Dimitri, P.R. Edwards, G.T. Abbott, Countess of Chester Hospital, Chester (15); D.J. Higman, A. Vohra, University Hospital Coventry, Coventry (8); S.

Ashley, C. Robottom, Derriford Hospital, Plymouth (2); M.G. Wyatt, J.D.G. Rose, Freeman Hospital, Newcastle (121);

K. Daly, D. Byrne, R. Edwards, Gartnavel General Hospital, Glasgow (12); K. Daly, D.P. Leiberman, D.H. McCarter, Glasgow Royal Infirmary, Glasgow (19); B. Modarai, P.R. Taylor, J.F. Reidy, Guy’s and St. Thomas’ Hospital, London (124); P. McCollum, A.R. Wilkinson, D.F. Ettles, Hull Royal Infirmary, Hull (29); A.E. Clason, G.L.S. Leen, James Cook University Hospital, Middlesborough (19); N.V. Wilson, M. Downes, Kent and Canterbury Hospital, Canterbury (1); J.

Abraham, S.R. Walker, J.M. Lavelle, Lancaster General Infirmary, Lancaster (12); M.J. Gough, S. McPherson, Leeds General Infirmary, Leeds (38); D.J.A. Scott, D.O. Kessell, Leeds St. James’s Hospital, Leeds (11); R. Naylor, R. Sayers, N.G. Fishwick, Leicester Royal Infirmary, Leicester (148); S. Vallabhaneni, P.L. Harris, D.A. Gould, Liverpool Royal Hospital, Liverpool (143); J.V. Smyth, M.G. Walker, N.C. Chalmers, Manchester Royal Infirmary, Manchester (96); A.

Garnham, M.A. Collins, New Cross Hospital, Wolverhampton (1); S. Thomas, J.D. Beard, P.A. Gaines, Northern General Hospital, Sheffield (77); M.Y. Ashour, R. Uberoi, Queen Elizabeth Hospital, Gateshead (18); S. Macsweeney, B.

Braithwaite, S.C. Whitaker, Queen’s Medical Centre, Nottingham (116); J.N. Davies, S. Travis, Royal Cornwall Hospital, Truro (26); G. Hamilton, A. Platts, M. Davis, Royal Free Hospital, London (42); A. Shandall, B.A. Sullivan, Royal Gwent Hospital, Newport (1); S. Sarkar, M. Sobeh, M. Matson, Royal London Hospital, London (7); A.D. Fox, R. Orme, Royal Shrewsbury Hospital, Shrewsbury (7); W. Yusef, T. Doyle, Royal Sussex County Hospital, Brighton (6); J. Budd, M.

Horrocks, J. Hardman, Royal United Hospital, Bath (34); D. Harkin, P.H.B. Blair, P.K. Ellis, Royal Victoria Hospital, Belfast (46); G. Morris, A. Odurny, Southampton General Hospital, Southampton (39); A. Tiwari, R. Vohra, M. Duddy, Selly Oak Hospital, Birmingham (22); M. Thompson, T.M.L. Loosemore, A.M. Belli, R. Morgan, St. George’s Hospital, London (54); O. Agu, M. Adiseshiah, J.A.S. Brookes, University College Hospital, London (69); C.N. McCollum, R.

Ashleigh, University Hospital of South Manchester, Manchester (127);

Trial Coordinators: M. Aukett, C. Bailey, S. Baker, E. Barbe, G. Bate, N. Batson, J. Bell, J. Blundell, D. Boardley, S. Boyes, H. Brooks, O. Brown, J. Bryce, J. Burrough, M. Carmichael, T. Chance, S. Clarke, J. Coleman, C. Cosgrove, G. Curran, L.

Dabee, L. Dali-Kemmery, A. Datson, M. Davis, T. Dennison, C. Devine, N. Dewhirst, B. Errington, H. Fairey, H. Farrell, C.

Fisher, P. Fulford, M. Gough, C. Graham, C. Harrison, R. Hooper, G. Horne, L. Horrocks, B. Hughes, T. Hutchings, M.

Ireland, C. Judge, L. Kelly, J. Kemp, A. Kite, M. Kivela, M. Lapworth, C. Lee, L. Linekar, A. Mahmood, L. March, J.

Martin, N. Matharu, K. McGuigen, P. Morris-Vincent, S. Murray, A. Murtagh, J. Myerscough, G. Owen, V. Ramoutar, C.

Rippin, J. Rowley, L. Sequeira, J. Sinclair, S. Spencer, V. Taylor, H. Thompson, C. Tomlinson, S. Ward, V. Wealleans, J.

West, K. White, J. Williams, L. Wilson.

Methods for per protocol and causal analyses

A per protocol analysis was performed on the patients who had complied with their randomised allocation. In the group randomised to EVAR, per protocol patients were defined as those who had an elective EVAR attempted even if they subsequently converted to open repair during the primary procedure in theatre. Patients who died without aneurysm repair or had an emergency repair were included as per-protocol patients. Patients who had elective open repair in the EVAR group were censored at aneurysm repair. In the group randomised to no intervention, per protocol patients were defined as those who remained without aneurysm repair at the end of the study or who had emergency repair as a result of rupture. Patients undergoing any type of elective aneurysm repair in the no intervention group were censored at the time of repair.

Since patients in the no intervention group who switched to EVAR were significantly more fit at baseline than patients assigned to EVAR who underwent repair (1) a per-protocol analysis could potentially be biased in favour of endovascular repair. A causal analysis was therefore also undertaken to obtain a randomisation-based efficacy estimate using a rank-preserving structural failure time model (RPSFTM) (2). The RPSFTM relates the observed time-to-events in the no intervention group to potential outcomes; the times that would have been observed had treatment not occurred. Patients in the No Intervention group were defined to come “on-treatment” at the time they underwent an elective operation, the EVAR group were assumed to be “on-treatment” from the time of randomisation. Re-censoring was undertaken as described by White et al. where censoring was allowed up to the administrative censoring date of 30

^th

June 2015 (3).

Supplementary information on defining re-interventions and censoring criteria

Re-interventions recorded during follow-up included those that took place during primary

admission and subsequent admissions. The date of any re-intervention during the primary

admission was taken to be the midpoint between the date of admission and the date of

discharge or in-hospital death. For all patients without a follow-up in 2014/15, the date of

last follow-up was used for censoring re-interventions. Censoring dates for mortality were

the date of death or 30

^th

June 2015, the date to when mortality flagging information from

NHS Digital was complete (4).

Table S1: Baseline characteristics of patients in the EVAR trial 2

Baseline characteristics by randomised group for EVAR trial 2

Baseline characteristic * EVAR

N=197

No intervention N=207

Age (years) 77.2 (6.3) [0] 76.4 (6.7) [0]

Number of males (%) 168 (85) [0] 179 (86) [0]

AAA diameter (cm) 6.8 (1.0) [0] 6.7 (1.0) [0]

Body Mass Index (Kg/m

²

) 26.4 (5.0) [1] 26.5 (4.4) [1]

Diabetes (%) 30 (15) [2] 29 (14) [2]

Smoking status (%) Current

Past Never

[0]

33 (17) 152 (77)

12 (6)

[0]

37 (18) 156 (75)

14 (7) History of cardiac disease # (%) 132 (67) [0] 153 (74) [0]

Systolic blood pressure (mmHg) 140 (20) [0] 139 (23) [0]

Diastolic blood pressure (mmHg) 79 (12) [0] 79 (12) [3]

Ankle-brachial pressure index

(mean of both legs) 0.99 (0.20) [10] 0.98 (0.19) [8]

Forced expiration volume in 1 second (L)

1.6 (0.6) [7] 1.7 (0.7) [4]

Serum creatinine (μmol/L) * 107 (90-134) [0] 112 (94-140) [2]

Serum cholesterol (mmol/L) 4.8 (1.2) [13] 4.8 (1.1) [7]

Statin use (%) 82 (42) [1] 86 (42) [0]

Aspirin use (%) 114 (58) [1] 114 (55) [0]

* Continuous variables presented as mean (standard deviation) apart from creatinine which is presented as median (interquartile range) as data were positively skewed. Categorical variables presented as number (%).

Data in squared brackets indicate number of patients with missing data.

# Cardiac disease defined as previous history of any of the following: myocardial infarction, angina, cardiac revascularisation, cardiac valve disease, significant arrhythmia or uncontrolled congestive cardiac failure.

Table S2: Causes of death by period since randomisation

Cause of death EVAR No repair

Randomisation to 6 months N=24 N=19

AAA-related*

AAA rupture (primary) Coronary heart disease Stroke Other (incl. PAD) Cancer, Lung Cancer, Other Respiratory Renal Other Secondary AAA rupture Unknown

8 7 2 0 0 1 0 5 0 1 0 0

1 8 5 2 0 0 0 1 1 1 0 0

6 months to 4 years N=92 N=108

AAA-related*

Primary AAA rupture Coronary heart disease Stroke Other (incl. PAD) Cancer, Lung Cancer, Other Respiratory Renal Other Secondary AAA rupture Unknown

3 6 30 3 0 7 14 19 2 7 1 0

0 35 32 2 3 3 11 9 3 8 0 2

4 years to 8 years N=49 N=41

AAA-related*

Primary AAA rupture Coronary heart disease Stroke Other (incl. PAD) Cancer, Lung Cancer, Other Respiratory Renal Other Secondary AAA rupture Unknown

0 0 11 1 0 4 8 15 1 9 0 0

3 9 12 0 0 4 5 5 0 3 0 0

> 8 years N=22 N=25 AAA-related*

AAA rupture (primary) Coronary heart disease Stroke Other (incl. PAD) Cancer, Lung Cancer, Other Respiratory Renal Other Secondary AAA rupture Unknown

0 0 2 0 3 1 5 8 0 1 2 0

0 0 11 1 0 1 4 3 0 3 1 1

*within 30 days of AAA repair or aneurysm-related re-intervention

Table S3: Hazard ratios comparing EVAR vs. no intervention for three pre-specified subgroups (age, sex, aneurysm diameter) and three exploratory subgroups (body mass

index, FEV

1

(% predicted), eGFR).

Baseline characteristic Rate per 100-person years Hazard ratio (EVAR vs. No Intervention)

Interaction p-value EVAR No Intervention

Any death Age (years)

<76.8

>76.8

19.8 26.0

18.2 27.5

1.10 (0.82, 1.47) 0.95 (0.72, 1.25)

0.40 Sex

Male Female

22.8 21.6

21.4 27.0

1.08 (0.87, 1.34) 0.78 (0.46, 1.33)

0.27 AAA diameter (cm)

<6.4cm 6.4cm

19.0 26.6

20.3 24.2

0.94 (0.70, 1.26) 1.11 (0.84, 1.47)

0.11 Body Mass Index (Kg/m²)

<25 27.8

19.4

22.7 21.7

1.24 (0.92, 1.68) 0.89 (0.68, 1.17)

0.25 FEV1 (% predicted)

<65 65

23.0

22.3 24.2

20.0

0.95 (0.71, 1.26) 1.13 (0.84, 1.51)

0.72

eGFR

<60 60

26.5 19.6

26.4 17.7

1.00 (0.76, 1.31) 1.13 (0.83, 1.53)

0.75 Aneurysm-related death

Age (years)

<76.8

>76.8

2.4 4.3

5.4 8.0

0.43 (0.21, 0.87) 0.57 (0.31, 1.05)

0.78 Sex

Male Female

3.3 3.3

5.9 10.6

0.55 (0.33, 0.90) 0.33 (0.11, 1.04)

0.44 AAA diameter (cm)

<6.4cm 6.4cm

3.0 3.6

5.3 7.9

0.59 (0.30, 1.15) 0.44 (0.23, 0.82)

0.74

Body Mass Index (Kg/m²)

<25 3.5

3.1

7.6 5.5

0.45 (0.22, 0.89) 0.58 (0.31, 1.08)

0.64 FEV1 (% predicted)

<65 65

3.7

3.2 7.0

5.5

0.55 (0.29, 1.03) 0.56 (0.28, 1.12)

0.73

eGFR (ml/min/1.73m²)

<60 60

5.0 1.9

7.9 5.2

0.64 (0.36, 1.14) 0.36 (0.17, 0.79)

0.042

For continuous variables results are presented divided at the median or clinically relevant cut-points (BMI, eGFR).

Ɨ P-value from a Cox regression model with a test of interaction between randomised group and the covariate as interest (keeping age, aneurysm diameter, body mass index, FEV

1

(% predicted) and eGFR as continuous).

Table S4: Comparison of trial results based on intention-to-treat, per-protocol and causal analyses.

Endovascular

Repair No Repair Hazard Ratio (95% CI) P

ValueƗ no. / person-years.

(rate/100 person-yr) Unadjusted Adjusted

(primary*, secondary**) Any death

Intention to treat 187/827 (22.6) 194/879 (22.1) 1.03 (0.84, 1.26) 1.06 (0.86, 1.30)

1.07 (0.86, 1.34) 0.52 Per-protocol 143/816 (17.5) 126/507 (24.8) 0.76 (0.59, 0.97) 0.83 (0.65, 1.07)

0.82 (0.63, 1.07) 0.14

Causal analysis* - 1.05 (0.74, 1.50) 1.08 (0.80, 1.47)

1.10 (0.82, 1.47)

0.52

Aneurysm- related death

Intention to treat 27/827 (3.3) 57/879 (6.5) 0.50 (0.32, 0.80) 0.55 (0.35, 0.88) 0.55 (0.34, 0.91)

0.019 Per-protocol 25/816 (3.1) 50/507 (9.9) 0.37 (0.23, 0.61) 0.43 (0.26, 0.70)

0.41 (0.24, 0.69) 0.0008

Causal analysis* - 0.41 (0.23, 0.75) 0.46 (0.25, 0.85)

0.46 (0.24, 0.88) 0.019

* Causal analyses use a randomisation-based efficacy estimate (rank-preserving structural failure

time model).

Table S5: Re-intervention according to time since randomisation

EVAR

N=197

No repair N=207 Any reintervention,

N pts (N reinterventions)

38 (54) 15 (21)

Time of reintervention

Randomisation to 6 months

26 6

6 months to 4 years

20 8

4 years to 8 years

8 4

Beyond 8 years 0

3

Type of reintervention

Added stent

18 4

Staple or Ligation 0 0

Embolisation (of endoleak)

9 2

Sclerosis of endoleaks 0 0

Conversion to OR

1 2

Other

6 2

Known aneurysmal extension

above or below original graft 0

1

Re-intervention for thrombosis

of graft limb 0 0

Re-intervention for Graft

infection 0

1

Incisional hernia 0 0

False femoral aneurysm 0

1

Minor re-intervention

2 1

Femoro-femoral crossover

3 1

FEVAR 0

1

Axillo – bi-femoral graft 0 0

Distal limb procedure/

revascularisation

11 2

Re-operation of open repair

1 0

Replacement stent graft 0

2

Further open abdominal

surgery in primary admission

3 0

Amputation 0 0

Unknown 0

1

Centres were asked to recall all patients for a final follow-up in 2014. Only 21 out of 52 patients in the EVAR group that were still alive in September 2009 had a follow-up. 24 out of 46 patients in the no intervention group that were still alive in September 2009 had a follow-up visit.

Table S6: All reinterventions from any relevant procedure according to time since randomisation.

Endovascular Repair (N=197)

No intervention

(N=207) Hazard Ratio (95% CI) P

ValueƗ No. unique reintervention

episodes* /total no. p-years (rate/100 person-yr)

Unadjusted Adjusted

(primary*, secondary**) Any

reintervention

All patients 47/717 (6.6) 21/768 (2.7) 2.39 (1.29, 4.41) 2.49 (1.35, 4.59) 2.66 (1.41, 5.00)

0.003 Time since

randomization

0-6 mo 23/91 (25.3) 6/100 (6.0) 4.10 (1.50, 11.22) 4.31 (1.53, 12.10)

4.94 (1.65, 14.81) 0.004

> 6 mo- 4 yr 16/416 (3.8) 8/448 (1.8) 2.16 (0.84, 5.55) 2.15 (0.80, 5.78)

2.56 (0.90, 7.29) 0.077

> 4yr 8/210 (3.8) 7/220 (3.2) 1.18 (0.41, 3.40) 1.28 (0.47, 3.50)

1.24 (0.41, 3.77) 0.70

* reinterventions that occur on separate days (7 reinterventions occurred on the same day as another reintervention).

References

1. The UK EVAR Trial Investigators. Endovascular repair of aortic aneurysm in patients physically ineligible for open repair. The New England journal of medicine. 2010;

362(20):1872-80

2. Robins JM, Tsiatis AA. Correcting for non-compliance in randomised trials using rank preserving structural failure time models. Comm Stats Theory Meth 1991; 20(8):

2609-2631

3. White IR, Babiker AG, Walker S et al. Randomisation-based methods for correcting for treatment changes: examples from the Concorde trial. Stat Med 1999; 18: 2617- 2634

4. https://www.digital.nhs.uk/