Jorg Lucas de Bruin · prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op vrijdag 7 juni 2019 om 13.45

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Dream on

de Bruin, J.L.

2019

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citation for published version (APA)de Bruin, J. L. (2019). Dream on: Long-term results comparing open and endovascular abdominal aorticaneurysm repair.

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https://research.vu.nl/en/publications/ed8e6ab6-d98f-4537-9176-1c2b7a9534ae

Jorg Lucas de Bruin

DREAM ONJorg Lucas de Bruin

The DREAM-trial was supported by a grant (OG 98-068) from the Netherlands National Health Insurance Council.

Financial support for the publication of this thesis by Julius Center for Health Science and Primary Care is gratefully acknowledged..

ISBN: 978-94-6375-396-8

Lay-out: Nikki Vermeulen - RidderprintPrinted by: Ridderprint - www.ridderprint.nl

© J.L. de Bruin, 2019

VRIJE UNIVERSITEIT

DREAM ONLong-term results comparing open and

endovascular abdominal aortic aneurysm repair

ACADEMISCH PROEFSCHRIFT

ter verkrijging van de graad Doctoraan de Vrije Universiteit Amsterdam,op gezag van de rector magnificus

prof.dr. V. Subramaniam,in het openbaar te verdedigen

ten overstaan van de promotiecommissievan de Faculteit der Geneeskunde

op vrijdag 7 juni 2019 om 13.45 uurin de aula van de universiteit,

De Boelelaan 1105

door

Jorg Lucas de Bruin

geboren te Amsterdam

promotoren: prof.dr. J.D. Blankensteijn prof.dr. D.E. Grobbee

copromotor: dr. M. Prinssen

CONTENTS

Chapter 1 Introduction 7

Chapter 2 Long-term outcome of open or endovascular repair of 13 abdominal aortic aneurysm. N Engl J Med. 2010 May 20;362(20):1881-9.

Chapter 3 Statin therapy is associated with improved survival after 27 endovascular and open aneurysm repair. J Vasc Surg. 2014 Jan;59(1):39-44.e1.

Chapter 4 Predicting reinterventions after open and endovascular aneurysm 39 repair using The St George’s Vascular Institute score. J Vasc Surg. 2016 Jun;63(6):1428-1433.e1.

Chapter 5 Residual infrarenal aortic neck following endovascular and 53 open aneurysm repair. Eur J Vasc Endovasc Surg. 2012 Apr;43(4):415-8.

Chapter 6 Renal function 5 years after open and endovascular aortic 63 aneurysm repair from a randomized trial. Br J Surg. 2013 Oct;100(11):1465-70.

Chapter 7 Quality of life from a randomized trial of open and endovascular 75 repair for abdominal aortic aneurysm. Br J Surg. 2016 Jul;103(8):995-1002.

Chapter 8 Summary and General discussion 91

List of publications 105

Dankwoord 109

Curriculum Vitae 112

Introduction

Chapter 1

1

INTRODUCTION | 9

Endovascular aneurysm repair (EVAR) has evolved to be the first line of treatment of Abdominal Aortic Aneurysms (AAA). 1, 2 This is supported by three randomized trials showing the perioperative mortality and morbidity benefits of endovascular repair compared to open repair. 3, 4, 5 However, these perioperative benefits do not appear to sustain beyond two years after surgery. 5, 6, 7, 8 In particular, cardiovascular deaths tend to contribute to this “catch-up” mortality during the first two years after aneurysm repair in the endovascular group. 11

In addition, concerns remain regarding the lack of durability of aortic endografts which may result in increased risk of late rupture, re-interventions and associated mortality.9, 10

Consequently, long-term outcomes of randomized trials are considered crucial in the decision as to which treatment option a patient should be offered. 8, 9, 10

The objective of this thesis is to answer the following question:

‘Which treatment is preferable for patients suitable for both Endovascular and Open aneurysm repair, considering long-term outcomes?’

This question can be broken up into several sub-questions:

- Is endovascular repair as durable as open repair, and is long-term mortality equal for both techniques?

- Which factors are associated with long-term survival in these, cardiovascular burdened, patients?

- How can patients at risk of secondary intervention after abdominal aortic aneurysm repair be identified?

- What is the effect of endovascular and open aneurysm repair on renal function?

- What is the influence of endovascular and open aneurysm repair on Quality of Life?

Chapter 2 describes the long-term results regarding mortality and durability comparing open and endovascular aneurysm repair.

Cardiovascular deaths in the endovascular treated group appear to contribute to the “catch-up” mortality during the first two years after aneurysm repair. 11 Several studies have suggested the beneficial effect of statin therapy reducing cardiovascular

10 | CHAPTER 1

complications and deaths immediately after vascular surgery. 12-18 To identify the association of pre-operative factors with survival, a post-hoc analysis was performed, described in Chapter 3.

The Achilles heel of endovascular aneurysm repair remains the durability of the aneurysm sac exclusion. 5, 6, 7, 8, 9, 19 Endoleak or migration with subsequent re-intervention and risk of rupture are more frequent after endovascular repair compared to open repair. 5, 6, 7, 8,

9, 19 After open repair, aneurysm related interventions are less common: in about 1.7% of the patients four years after surgery. 27 Laparotomy-related interventions are more common after open repair (±10%). 27 Chapter 4 describes an analysis to identify patients at risk of secondary intervention after abdominal aortic aneurysm repair using the St George’s Vascular Index (SGVI) score.

Durability of both techniques is dependent on the success of the surgeon’s planning and technique.28, 29 Treating the aneurysmal neck seams pivotal in both strategies. Leaving a part of the aortic neck untreated could lead to inferior sealing or para-anastomotic aneurysms in endovascular and open repair, respectively. An analysis determining the length of the residual infrarenal neck and the comparison between endovascular and open repair is described in Chapter 5. Since the introduction of the endovascular technique, renal function after aneurysm repair has been a concern. Renal failure is a major public health problem associated with high costs, poor outcomes 20-22 and impaired survival, especially after vascular surgery. 23-26 In Chapter 6, the influence of each treatment strategy on renal function after abdominal aortic aneurysm repair is examined and compared.

Morbidity and mortality are long standing key markers of surgical outcomes. However, in line with patient-centered health care, more subjective measures, such as Quality of Life (QoL) and Health Status (HS) are increasingly important. Chapter 7 describes the long-term results of the patient-centered Health Related Quality of Life and Health Status after endovascular and open aneurysm repair.

1

INTRODUCTION | 11

REFERENCES

1 Parodi JC, Palmaz JC, Barone HD. Transfemoral intraluminal graft implantation for abdominal aortic aneurysms. Ann Vasc Surg. 1991 Nov;5(6):491-9.

2 Volodos NL, Karpovich IP, Troyan VI, Kalashnikova YuV, Shekhanin VE, Ternyuk NE, Neoneta AS, Ustinov NI, Yakovenko LF. Clinical experience of the use of self-fixing synthetic prostheses for remote endoprosthetics of the thoracic and the abdominal aorta and iliac arteries through the femoral artery and as intraoperative endoprosthesis for aorta reconstruction. Vasa Suppl. 1991;33:93-5

3 Prinssen M, Verhoeven EL, Buth J, et al; A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2004;351(16):1607-1618.

4 Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet 2004;364(9437):843-848.

5 Lederle FA, Freischlag JA, Kyriakides TC, Padberg FT Jr, Matsumura JS, Kohler TR, Lin PH, Jean-Claude JM, Cikrit DF, Swanson KM, Peduzzi PN; Open Versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study Group. Outcomes following endovascular vs open repair of abdominal aortic aneurysm: a randomized trial. JAMA. 2009 Oct 14;302(14):1535-42.

6 Blankensteijn JD, de Jong SE, Prinssen M, et al; Two-year outcomes after conventional or endovascular repair of abdominal aortic aneurysms. N Engl J Med 2005; 352(23):2398-2405.

7 Evar trial participants. Endovascular aneurysm repair versus open repair in patients with abdominal aortic aneurysm (EVAR trial 1): randomised controlled trial. Lancet 2005;365 (9478):2179-2186.

8 Cronenwett JL. Endovascular aneurysm repair: important mid-term results. Lancet. 2005 Jun 25-Jul 1;365(9478):2156-8.

9 Leurs LJ, Buth J, Laheij RJ. Long-term results of endovascular abdominal aortic aneurysm treatment with the first generation of commercially available stent grafts. Arch Surg 2007;142(1):33-41.

10 Lederle FA. Endovascular repair of abdominal aortic aneurysm--round two. N Engl J Med 2005;352(23):2443-2445.

11 Brown LC, Thompson SG, Greenhalgh RM, Powell JT; Endovascular Aneurysm Repair trial participants. Incidence of cardiovascular events and death after open or endovascular repair of abdominal aortic aneurysm in the randomized EVAR trial 1. Br J Surg. 2011;98:935-942.

12 Poldermans D, Bax JJ, Kertai MD, Krenning B, Westerhout CM, Schinkel AF, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation. 2003;107:1848-1851.

13 Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC, Puech-Leão P, et al. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg. 2004;39:967-975.

14 O’Neil-Callahan K, Katsimaglis G, Tepper MR, Ryan J, Mosby C, Ioannidis JP, et al. Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery: the Statins for Risk Reduction in Surgery (StaRRS) study. J Am Coll Cardiol. 2005;45:336-342.

15 Kertai MD, Boersma E, Westerhout CM, Klein J, Van Urk H, Bax JJ, et al. A combination of statins and beta-blockers is independently associated with a reduction in the incidence of perioperative mortality and nonfatal myocardial infarction in patients undergoing abdominal aortic aneurysm surgery. Eur J Vasc Endovasc Surg. 2004;28:343-352.

12 | CHAPTER 1

16 Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MR, et al. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med. 2009;361:980-989.

17 Le Manach Y, Ibanez Esteves C, Bertrand M, Goarin JP, Fléron MH, Coriat P, et al. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing vascular surgery. Anesthesiology. 2011;114:98-104.

18 McNally MM, Agle SC, Parker FM, Bogey WM, Powell CS, Stoner MC. Preoperative statin therapy is associated with improved outcomes and resource utilization in patients undergoing aortic aneurysm repair. J Vasc Surg. 2010;51:1390-1396.

19. Schanzer A, Greenberg RK, Hevelone N, Robinson WP, Eslami MH, Goldberg RJ, Messina L. Predictors of abdominal aortic aneurysm sac enlargement after endovascular repair. Circulation. 2011 Jun 21;123(24):2848-55.

20 Meguid El Nahas A, Bello AK. Chronic kidney disease: the global challenge. Lancet 2005; 365: 331¬¬–340.

21 Hemmelgarn BR, Manns BJ, Lloyd A, James MT, Klarenbach S, Quinn RR et al.; Alberta Kidney Disease Network. Relation between kidney function, proteinuria, and adverse outcomes. JAMA 2010; 303: 423–429.

22 James MT, Hemmelgarn BR, Tonelli M. Early recognition and prevention of chronic kidney disease. Lancet 2010; 375: 1296–1309.

23 Brady AR, Fowkes FG, Greenhalgh RM, Powell JT, Ruckley CV, Thompson SG. Risk factors for postoperative death following elective surgical repair of abdominal aortic aneurysm: results from the UK Small Aneurysm Trial. On behalf of the UK Small Aneurysm Trial participants. Br J Surg 2000; 87: 742–749.

24 van Eps RG, Leurs LJ, Hobo R, Harris PL, Buth J; EUROSTAR Collaborators. Impact of renal dysfunction on operative mortality following endovascular abdominal aortic aneurysm surgery. Br J Surg 2007; 94: 174–178.

25 Baas AF, Janssen KJ, Prinssen M, Buskens E, Blankensteijn JD. The Glasgow Aneurysm Score as a tool to predict 30-day and 2-year mortality in the patients from the Dutch Randomized Endovascular Aneurysm Management trial. J Vasc Surg 2008; 47: 277–281.

26 Patel VI, Lancaster RT, Mukhopadhyay S, Aranson NJ, Conrad MF, LaMuraglia GM et al. Impact of chronic kidney disease on outcomes after abdominal aortic aneurysm repair. J Vasc Surg 2012; 56: 1206–1213.

27 Schermerhorn ML, O’Malley AJ, Jhaveri A, Cotterill P, Pomposelli F, Landon BE. Endovascular vs. open repair of abdominal aortic aneurysms in the Medicare population. N Engl J Med. 2008 Jan 31;358(5):464-74.

28 Sobocinski J, Chenorhokian H, Maurel B, Midulla M, Hertault A, Le Roux M, Azzaoui R, Haulon S. The benefits of EVAR planning using a 3D workstation. Eur J Vasc Endovasc Surg. 2013 Oct;46(4):418-23.

29 Conrad MF, Crawford RS, Pedraza JD, Brewster DC, Lamuraglia GM, Corey M, Abbara S, Cambria RP.Long-term durability of open abdominal aortic aneurysm repair. J Vasc Surg. 2007 Oct;46(4):669-75.

Long-term outcome of open or endovascular repair of abdominal aortic aneurysm

Chapter 2

2

LONG-TERM OUTCOME | 15

BACKGROUND

Randomized trials have shown that endovascular repair offers a perioperative survival benefit over open repair for patients with a large abdominal aortic aneurysm. However, this advantage is not sustained beyond two years after surgery.1-4 There is concern that endovascular repair lacks durability, with the possibility of an increased risk of late rupture,5 and that more reinterventions are required in patients undergoing this technique. Long-term outcome data from these trials is considered to be of crucial importance in deciding which treatment option a patient should be offered.6,7 To date, only limited data beyond two years after randomization has been reported. To provide long-term data, we analyzed the results of the Dutch Randomized Endovascular Aneurysm Repair (DREAM) trial after a median of 6.4 years.1,3

METHODS

The design and methods of this trial have been described in detail previously.8 In brief, the DREAM trial was a multicenter, randomized trial conducted at 26 centers in the Netherlands and four centers in Belgium. The institutional review board at each center approved the original trial protocol and the follow-up extension. The study was performed according to the principles of the Declaration of Helsinki. The trial was funded by a grant from the NetherlandsNational Health Insurance Council. No support was provided by pharmaceutical or medical-device companies. The sponsor had no role in the design or conduct of the study; in the collection, management, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.

Patients who had an abdominal aortic aneurysm measuring at least five cm in diameter and who were considered suitable candidates for either open or endovascular repair were enrolled after providing written informed consent. Suitability for endovascular repair was primarily determined by means of endograft-dependent anatomical criteria, whereas suitability for open repair was determined by an internist or cardiologist. Patients who required emergency aneurysm repair were excluded from the trial, as were patients with inflammatory aneurysms, anatomical variations (e.g., horseshoe kidney), connective-tissue disease, a history of organ transplantation, or a life expectancy of less than two years. Randomization to either procedure was carried out centrally with the use of a computer-generated, permuted-block sequence and stratified according to study center in blocks of four patients. The primary informed consent covered two years of close follow-up for all patients. For this long-term analysis, a second written informed

16 | CHAPTER 2

consent was requested from all patients who had completed the initial two years of follow-up. Patients were asked to provide consent for continued acquisition of follow-up data for the purpose of this study and for our sending twice-yearly questionnaires on their quality of life and use of medical services. Patients were informed that the follow-up protocol after the second postoperative year would not require extra studies for trial purposes and would involve only the collection of data regarding routine clinical care.

Follow-up visits for the initial phase of the trial were scheduled 30 days and six, 12, 18, and 24 months after the procedure. After the initial two years of close follow-up, patients received a questionnaire every six months requesting information about the status of their mental and physical health, as well as information about visits to a general practitioner or other physicians and all hospital admissions. Follow-up for patients in the endovascular repair group included a yearly follow-up visit and the performance of computed tomography (CT). Patients in the open repair group were advised to see their physicians annually, but they were not actively recruited for follow-up visits during the third and fourth years after surgery. All patients were contacted by telephone five years postoperatively and were invited for a follow-up visit with a CT scan. Medical records were used to confirm the information that patients had provided. All data was submitted to the trial-coordination center at the Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, the Netherlands. For the current analysis, data acquisition was stopped on February 1, 2009. For all analyses, data were censored after the last follow-up contact or at the time the last questionnaire was returned. Patients who had declined further participation at two years or who were initially lost to follow-up were contacted directly or through their relatives or physicians. In addition, from November 2008 through February 2009, all records were scrutinized for information about reinterventions and causes of death. The information obtained in this way was incorporated into the analysis of crude survival and causes of death.

The long-term primary outcomes were rates of death from any cause and reintervention. An outcome-adjudication committee, consisting of five vascular surgeons, classified the causes of death and reinterventions in a blinded fashion and independently from one another. Disagreements were resolved in a plenary consensus meeting. The causes and exact dates of death were determined by reviewing death certificates and, if necessary, by contacting the involved physicians (general practitioners, surgeons, and other specialists) and patients’ relatives. In-hospital death was defined as any death occurring within 30 days after the original procedure or any death occurring more than 30 days after the original procedure but during the same hospital admission. We distinguished between cardiovascular causes of death (myocardial infarction, congestive heart failure, cardiac arrest, stroke, and ruptured aneurysm) and noncardiovascular causes of death

2


(cancer, pulmonary conditions, and miscellaneous disorders). A reintervention was defined as any surgical or endovascular procedure that was related to the primary aneurysm repair procedure. The decision to perform a secondary intervention was made by the individual surgeon. Indications for reinterventions were classified into three groups: graft related indications (e.g., thrombo-occlusive disease, endoleak type 1 or endotension [pressure in the aneurysm sac without a detectable endoleak], endograft migration, prosthesis infection, graft-material failure, para-anastomotic aneurysm, and aneurysm rupture), wound-related indications (e.g., incisional hernia and wound infection), and local or systemic indications (e.g., bleeding, endoleak type 2, and ileus).All data was analyzed according to the intention-to-treat principle. The completeness of follow-up was calculated as the ratio of the total observed person-time of follow-up to the potential time of follow-up in the study for the two study groups.9 Kaplan–Meier analysis was used to calculate survival and other end points, and differences between groups were compared with the use of the log-rank test. All reported P values are two-sided and have not been corrected for multiple testing.

RESULTS

From November 2000 through December 2003, we randomly assigned 178 patients to undergo open repair and 173 to undergo endovascular repair (Fig. 1). Baseline characteristics are shown in Table 1. The mean age of the patients was 70 years, and 91.7% were male; 43.9% had concomitant cardiac disease. Six patients did not undergo aneurysm repair after randomization: four declined treatment (three in the open repair group and one in the endovascular repair group), one died from a ruptured abdominal aortic aneurysm before undergoing open repair, and one died from pneumonia before undergoing endovascular repair. There were eight in-hospital deaths after open repair and two after endovascular repair (Fig. 1). The median follow-up was 6.4 years (range, 5.1 to 8.2). All patients were followed for five years, 79% for six years, and 53% for seven years. The completeness of follow-up was 99.3% (11,589/11,673 months) for open repair and 99.7% (11,193/11,232 months) for endovascular repair. At the date of censoring, 106 patients had died during follow-up after hospital discharge (51 in the open-repair group and 55 in the endovascular-repair group) (Fig. 1). Five years after randomization, CT was performed in approximately one fourth of patients in the open-repair group and in almost all patients in the endovascular-repair group.

Six years after randomization, the cumulative overall survival rates were 69.9% for open repair and 68.9% for endovascular repair, a difference of 1.0 percentage point (95% confidence interval [CI], −8.8 to 10.8; P = 0.97) (Fig. 2A). The increased perioperative

18 | CHAPTER 2

mortality in the open repair group was counterbalanced by a larger number of deaths after discharge in the endovascular-repair group. An analysis of the causes of death indicated that miscellaneous rather than cardiovascular causes accounted for the larger number of deaths after discharge among patients undergoing endovascular repair (Table 2).

351 Patients underwent randomization

(November 2000 – December 2003)

178 Were assigned to undergo open repair

173 Were assigned to undergo endovascular repair

4 Did not undergo assigned repair

3 Declined to participate 1 Died

174 Started aneurysm repair 169 Completed open repair

4 Completed EVAR 1 Aborted endovascular

171 Started aneurysm repair 167 Completed EVAR

1 Completed open repair 3 Had immediate conversion to

open repair

2 Did not undergo assigned repair

1 Declined to participate 1 Died

166 Were discharged from hospital 161 After open repair

4 After EVAR 1 After no repair

8 Died in hospital

115 Were still alive in February 2009

51 Died

169 Were discharged from hospital

165 After EVAR 4 After open repair

2 Died in hospital

114 Were still alive February 2009

55 Died

Figure 1 Enrollment and Outcomes

2


Table 1 Baseline Characteristics of the Patients *

Open repair Endovascular repairP Value

(n = 178) (n =173)

Age in years 69.6 ±6.8 70.7 ±6.6 0.13

Male Sex (%) 161 (90.4) 161 (93.1) 0.44

Patients with mild, moderate, or severe SVS/ISCVS risk factor score % †

Diabetes mellitus 9.6 10.4 0.86

Tobacco use 55.1 64.2 0.10

Hypertension 54.5 58.4 0.52

Hyperlipedemia 52.6 47.0 0.33

Carotid disease 15.2 14.5 0.88

Cardiac disease 46.6 41.0 0.33

Renal disease 8.4 7.5 0.85

Pulmonary disease 18.5 27.7 0.04

Sum of SVS/ISCVS risk-factor scores (SD) 4.5 ±2.5 4.4 ±2.5 0.61

FEV1 liters/sec (SD) 2.6 ±0.7 2.5 ±0.7 0.27

Body-mass index (SD) 26.6 ±4.1 26.3 ±3.4 0.47

ASA class (%)

I (healthy) 44 (24.7) 37 (21.4) 0.53

II (mild systemic disease) 110 (61.8) 122 (70.5) 0.09

III (severe systemic disease) 24 (13.5) 14 (8.1) 0.12

Medication use (%)

Beta-blocker 92 (51.7) 76 (43.9) 0.17

Statin 72 (41.9) 63 (37.3) 0.44

Antiplatelet agent 72 (40.4) 70 (40.5) 1.00

Angiotensin-converting-enzyme inhibitor 50 (28.1) 58 (33.5) 0.30

Calcium-channel blocker 32 (18.0) 30 (17.3) 0.89

Anticoagulant 27 (15.2) 20 (11.6) 0.35

* Plus–minus values are means ±SD. ASA denotes American Society of Anaesthesiologists, and FEV1 forced expiratory volume in 1 second. The body-mass index is the weight in kilograms divided by the square of the height in meters. Because of rounding, not all percentages total 100. † The Society for Vascular Surgery/International Society for Cardiovascular Surgery (SVS/ISCVS) risk-factor score ranges from 0 (no risk factors) to 3 (severe risk factors) for each of eight domains.7 Total scores range from 0 to 24, with higher scores indicating more risk factors. ‡ No data about statin use were available for six patients in the open-repair group and four patients in the endovascular repair group.

Six years after randomization, the cumulative rates of freedom from secondary interventions were 81.9% for open repair and 70.4% for endovascular repair, a difference of 11.5 percentage points (95% CI, 2.0 to 21.0; P = 0.03) (Fig. 2B). After open repair, the

20 | CHAPTER 2

most frequent reintervention was correction of an abdominal incisional hernia, whereas endovascular-repair reinterventions were most often performed because of endograft-related complications, such as endoleak and endograft migration (Table 3). In one patient who had crossed over from open to endovascular repair, reintervention because of an occluded endograft limb was complicated by a fatal myocardial infarction. In the open-repair group, nine patients required a second reintervention and two required a third reintervention. After endovascular repair, 14 patients required a second reintervention, and seven required a third reintervention. Endovascular procedures accounted for five of 41 reinterventions (12%) in the open-repair group and 25 of 69 reinterventions (36%) in the endovascular-repair group.

Table 2 Causes of Death after Open or Endovascular Aneurysm Repair

Cause of Death§ Before Surgery * In the Hospital After Discharge Overall

Open Repair

N=178

Endo vascular RepairN=173

Open Repair

N=174


Open Repair

N=166

Endo vascular Repair N=169

Open Repair

N=178


Number of patients

All causes 1 1 8 2 51 55 60 58

Cardiovascular causes 1 0 2 1 17 15 20 16

Myocardial Infarction 0 0 1 (1)† 1 4 4 5 5

Cardiac arrest 0 0 1 0 4 3 5 3

Congestive heart failure 0 0 0 0 4 5 4 5

Stroke 0 0 0 0 4 3 4 3

Ruptured aneurysm 1 0 0 0 1 0 2 0

Cancer 0 0 0 0 18 18 (1)† 18 18

Pulmonary causes 0 1 0 1 5 (2)† 5 (1)† 5 7

Miscellaneous 0 0 6 (1)† ‡ 0 4 § 10 ¶ 10 10

Unknown 0 0 0 0 7 7 7 7

* Two patients died before undergoing the assigned operation: one patient in the open-repair group, from a ruptured abdominal aortic aneurysm 49 days after randomization, and one patient with pulmonary fibrosis in the endovascular-repair group, from pneumonia 84 days after randomization. † The number in parentheses is the number of patients in whom the cause of death was confirmed on postmortem examination. ‡ The causes of death were infection of the prosthesis, anastomotic bleeding, ischemic bowel, intraoperative anaphylactic shock, multiorgan failure after repair of a burst abdomen, and progressive dementia. § The causes of death were sepsis from infection of the prosthesis, sepsis after acute pancreatitis and cholangitis, gastrointestinal bleeding, and renal failure from dehydration. ¶ The causes of death were sepsis from infection of the endograft (two patients), gastrointestinal bleeding (two patients), dehydration from obstructive bowel disease, suicide, complications of hip-fracture surgery, complications of diaphragmatic-hernia repair, pulmonary embolism, and liver failure associated with alcohol abuse.

2


A Survival

Number at RiskOpen repair 178 166 159 150 143 137 88 36Endovascular repair 173 166 156 143 133 128 83 39

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7

Pro

babi

lity

of S

urvi

val

Years after Randomization

Endovascular repair Open repair

P=0.97

B Freedom from reinterventions

Number at RiskOpen repair 178 152 139 128 118 111 73 29Endovascular repair 173 147 134 123 115 102 66 31

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7

Pro

babi

lity

of F

reed

om

From

Rei

nter

vent

ion


Endovascular repair Open repair

P<0.03

Figure 2 Kaplan-Meier Estimates of Survival (Panel A) and Freedom from Reintervention (Panel B).

22 | CHAPTER 2

Table 3 Indications for First Reintervention after Open or Endovascular Aneurysm Repair

IndicationOpen Repair

(N=178)Endovascular Repair

(N=173)Total

(N=351)

Number of Patients

Any Indication 30 48 78

Graft-related indication

Any 4 36 40

Thrombo-occlusive disease 3 12 15

Endoleak type 1* 0 12 12

Migration 0 7 7

Prosthesis infection 0 2 2

Endotension 0 1 1

Material Failure 0 1 1

Para-anastomotic aneurysm 1 0 1

Aneurysm Rupture 0 1 1

Wound-related causes

Any 15 3 18

Incisional hernia 14 0 14

Wound infection 1 2 3

Miscellaneous 0 1 1

Local or systemic causes

Any 11 9 20

Bleeding 5 2 7

Endoleak type 2* 2 † 6 8

Bowel resection or Ileus 3 ‡ 0 3

Miscellaneous § 1 1 2

* In endoleak type 1, which typically occurs early after surgery, an ineffective seal at the proximal or distal end of the endograft permits blood flow into the aneurysm sac. In endoleak type 2, retrograde flow from patent lumbar side branches causes flow into the aneurysm sac. † These two patients had crossed over from open repair to endovascular repair. ‡ Two resections were performed during the initial admission for open aneurysm repair. One patient underwent surgical repair for late bowel obstruction. § One patient underwent reintervention because of a mass around the endovascular graft, as seen on computed tomography, but no infection was found. Histologic analysis showed signs of fibrosis. The other patient underwent an embolectomy of the popliteal artery, which was not graft-related.

DISCUSSION

Our principal finding was that among patients with large abdominal aortic aneurysms, there was no significant difference between endovascular repair and open repair in the rate of overall survival at a median of 6.4 years. A small but significant difference in 30-day operative mortality in favour of endovascular repair had previously been reported in the DREAM trial and in two large, randomized trials.1,2,10 In two-year analyses of both

2


the DREAM trial3 and the United Kingdom Endovascular Aneurysm Repair 1 (EVAR 1) trial (Current Controlled Trials number, ISRCTN55703451),4 this apparent early benefit had already been lost. With the longer follow-up in our study, the rate of overall survival remained similar for the two procedures. Another finding was that endovascular repair was associated with a significantly higher rate of reintervention than with open repair. This observation supports the view that the short-term survival benefit of endovascular repair is achieved at the expense of long-term problems related to endograft durability. Although these problems do not seem to translate into a long-term disadvantage in overall survival, the risks associated with reintervention need to be assessed in larger studies. It is important to recognize that reintervention rates constitute a soft end point because the decision to perform a secondary procedure was at the discretion of the surgeon. However, the decisions of vascular surgeons in clinical practice are probably made on a similar basis.In 2005, investigators in the EVAR 1 trial reported a follow-up of four years for patients undergoing either open repair or endovascular repair.4 At that interval however, the number of patients at risk had dropped below 20% of those who had undergone randomization, and fewer than half the patients had been followed for three years or more. The recently published Open Versus Endovascular Repair (OVER) trial (ClinicalTrials.gov number, NCT00094575) reported two years of follow-up on 80% of randomized patients but no three-year results.10 However, problems arising from limited durability of endovascular aneurysm repair are not expected to occur in the first two postoperative years. In our analysis of the DREAM trial data, not a single patient was lost to follow-up, and all surviving patients were followed for at least five years after randomization. Retrospective hospital and population-based studies with nine years of follow-up after surgery have shown similar results.11-14 However, since these studies were not randomized, they all have a potential selection bias. The most important cause of bias is the potential association between the estimated short-term and long-term risks of death for a given patient, on the one hand, and the decision of the clinician to recommend open or endovascular repair, on the other. In theory, inferior durability of endovascular repair, when compared with open repair, could mitigate long-term survival outcomes and thereby negate the short-term survival benefit of endovascular repair or even result in increased long-term risk. The cluster of reinterventions that appeared in the fifth year after endovascular repair is particularly troubling and casts doubt on the durability of endovascular devices. In our study, reinterventions that were performed more than four years after aneurysm repair were required because of endograft migration, limb thrombosis, or endoleak (type 1 or 2). The reintervention for an endograft limb occlusion followed by death a few days later illustrates the potential for reintervention to decrease patients’ quality of life and increase the risk of aneurysm related death. Despite this concern, graft-related complications and aneurysm rupture

24 | CHAPTER 2

were not frequent causes of death in the long term. Therefore, we could detect no effect of graft complications on survival, a finding that may be a consequence of insufficient statistical power. Long-term and pooled analyses of the four randomized trials — DREAM, EVAR 1, OVER, and Aneurisme de L’aorte Abdominale: Chirurgie versus Endoprothese (ACE) 15 — could have enough power to address this issue. However, it is also important to note that since the initiation of these trials, endovascular devices and techniques have undergone further modification, and with increasing experience, physicians have revised their criteria for identifying suitable candidates for endovascular repair. These changes may reduce the risk of complications requiring reintervention and thus increase long-term survival after endovascular repair. Some limitations of our study should be noted. Because patients in the open repair group did not undergo CT in the third and fourth years after aneurysm repair, and because only about one fourth of patients in the open repair group underwent CT at five years (as compared with almost all patients in the endovascular repair group), ascertainment bias probably contributed to the finding of more graft-related problems in the endovascular repair group. Conversely, since it is not common practice to follow patients for more than six to 12 months after open repair, the elaborate follow-up protocol for all patients in the DREAM trial during the first two postoperative years may have led to an artificially high rate of early reintervention after open repair. Another limitation of our trial concerns the relatively wide confidence interval for the difference in the primary outcome. On the basis of this interval, our results are consistent with a survival rate in the open repair group that is as much as 10.8% higher or 8.8% lower than that in the endovascular repair group. This imprecision is the inevitable consequence of the initial sample size and the numbers of patients remaining alive after 6 years of follow-up. Not all patients with an abdominal aortic aneurysm are anatomically suitable for endovascular repair. Certain subgroups of patients (in terms of expected survival, coexisting illnesses, or various associated risk factors) may benefit more from one or the other type of aneurysm repair, but much larger trials or analysis of pooled data from the existing trials would be needed to identify these patients. Nevertheless, our study may help guide physicians and patients in choosing between open and endovascular repair, as our findings can be appraised in relation to various individual and personal circumstances. In conclusion, our comparison of endovascular repair of abdominal aortic aneurysm with open repair showed similar long-term survival 6 years after randomization. There was a higher rate of secondary interventions in the endovascular repair group.

2


REFERENCES

1. Prinssen M, Verhoeven 1. EL, Buth J, et al. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2004;351:1607-18.

2. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomized controlled trial. Lancet 2004;364:843-8.

3. Blankensteijn JD, de Jong SE, Prinssen M, et al. Two-year outcomes after conventional or endovascular repair of abdominal aortic aneurysms. N Engl J Med 2005;352:2398-405.

4. EVAR Trial Participants. Endovascular aneurysm repair versus open repair in patients with abdominal aortic aneurysm (EVAR trial 1): randomised controlled trial. Lancet 2005;365:2179-86.

5. Leurs LJ, Buth J, Laheij RJ. Long-term results of endovascular abdominal aortic aneurysm treatment with the first generation of commercially available stent grafts. Arch Surg 2007;142:33-41.

6. Lederle FA. Endovascular repair of abdominal aortic aneurysm — round two. N Engl J Med 2005;352:2443-5.

7. Cronenwett JL. Endovascular aneurysm repair: important mid-term results. Lancet 2005;365:2156-8.

8. Prinssen M, Buskens E, Blankensteijn JD. The Dutch Randomised Endovascular Aneurysm Management (DREAM) trial: background, design and methods. J Cardiovasc Surg (Torino) 2002;43:379-84.

9. Clark TG, Altman DG, De Stavola BL. Quantification of the completeness of follow-up. Lancet 2002;359:1309-10.

10. Lederle FA, Freischlag JA, KyriakidesTC, et al. Outcomes following endovascular vs open repair of abdominal aortic aneurysm: a randomized trial. JAMA 2009;302:1535-42.

11. Cao P, Verzini F, Parlani G, et al. Clinical effect of abdominal aortic aneurysm endografting: 7-year concurrent comparison with open repair. J Vasc Surg 2004; 40:841-8.

12. Schermerhorn M, O’Mally AJ, Jhaveri A, et al. Endovascular vs. open repair of abdominal aortic aneurysms in the Medicare population. N Engl J Med 2008; 358:464-74.

13. Brewster DC, Jones JE, Chung TK, et al. Long-term outcomes after endovascular abdominal aortic aneurysm repair: the first decade. Ann Surg 2006;244:426-38.

14. Peterson BG, Matsumura JS, Brewster DC, Makaroun MS. Five-year report of a multicenter controlled clinical trial of open versus endovascular treatment of abdominal aortic aneurysms. J Vasc Surg 2007;45:885-90.

15. Becquemin JP. The ACE trial: a randomized comparison of open versus endovascular repair in good risk patients with abdominal aortic aneurysm. J Vasc Surg 2009;50:222-4.

Statin therapy is associated with improved survival after endovascular and open aneurysm repair

Chapter 3

3

STATIN THERAPY AND SURVIVAL | 29

BACKGROUND

Randomized trials have shown that endovascular repair offers a perioperative survival benefit over open repair for patients with large abdominal aortic aneurysms (AAAs).1-3 However, this advantage is not sustained beyond two years after surgery.4 Cardiovascular deaths in the endovascular aneurysm repair group appear to contribute to this “catch-up” mortality during the first two postoperative years.5 Consequently, long-term survival is equal for both types of aneurysm repair,6,7 with cardiovascular and cancer as the main causes of death. A recent Danish study showed an increased risk for cardiovascular events and death after AAA repair compared with the general population,8 suggesting a potential benefit of both aspirin and a statin. In a systematic review, statin therapy was shown to improve all-cause survival after AAA repair, but this was a review of retrospective studies only.9-12 Several studies have suggested a beneficial effect of perioperative statin therapy in reducing cardiovascular complications and deaths directly after vascular surgery.14-20 To investigate the potential beneficial effect of statin therapy on long-term survival after aneurysm repair, a post-hoc analysis was performed on patients from the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial.

METHODS

A post-hoc analysis of the DREAM trial was performed. The design and methods of the trial have been described in detail.21 In summary, 351 patients referred to vascular surgery departments at 26 centers in The Netherlands and four centers in Belgium, with an AAA of at least five cm in diameter and considered suitable candidates for both techniques were randomly assigned to open or endovascular repair. The trial was conducted according to the Declaration of Helsinki and approved by the ethics committee of each participating hospital. All data were collected by the trial coordination center (Julius Center for Health Sciences and Primary Care, University Medical Center, Utrecht, The Netherlands). Patients were followed prospectively at 30 days and six, 12, 18, and 24 months after the procedure. After the initial two years of close follow-up, patients received a questionnaire every six months requesting information about the status of their mental and physical health, as well as information about visits to a general practitioner or other physicians and hospital admissions. Five years postoperatively, patients were contacted by telephone, and the information obtained was cross-referenced with their medical records. Between November 2008 and February 2009, all patient records were scrutinized for survival and causes of death. The causes of death were determined by reviewing death certificates, medical records, and, if necessary, by contacting involved physicians (general practitioners, surgeons, and other specialists)

30 | CHAPTER 3

and patients’ relatives. An outcome-adjudication committee, consisting of five vascular surgeons, classified the causes of death in a blinded fashion and independently from one another. Disagreements were resolved in a plenary consensus meeting. The causes of death were grouped into the following categories: cardiovascular (myocardial infarction, congestive heart failure, cardiac arrest, stroke), cancer, pulmonary, miscellaneous, and unknown. Patients who were on lipid-lowering medication at their inclusion in the trial (n = 135) were compared with those who were not (n = 216; Table I). At the time of the operation, we did not have missing data regarding statin use, therefore the analysis was done on all the patients. To compare these groups on survival, outcomes were estimated using Kaplan-Meier functions and compared using the logrank test. This trial was not designed to detect a difference between patients with or without statin therapy. Therefore, we performed a multivariable analysis, correcting for important confounding variables. The following variables were used in a multivariable analysis: age above 70, gender, aneurysm size above 70 mm, the need for reintervention, Society for Vascular Surgery/International Society for Cardiovascular Surgery risk factors (cardiac disease, pulmonary disease, renal disease, carotid artery disease, hypertension, diabetes mellitus, tobacco use), statin therapy, use of antiplatelet or anticoagulant agents, and use of b-blockers. The variables were mutually adjusted using a stepwise Cox regression analysis. Each individual variable was adjusted for randomization group in a primary model, and subsequently, each of the remaining variables were added to and removed from this model. The variable with the strongest influence on the primary regression coefficient was then added to the primary model, and the cycle was repeated until none of the remaining variables influenced the primary regression coefficient by more than 10%. In this way, a final multivariable model was created based on each individual variable. The hazard ratios (HRs) of the initial variable in all final models were reported as mutually adjusted HRs. In addition, the association with lipid-lowering medication and causes of death (grouped as cardiovascular, cancer, pulmonary, miscellaneous, and unknown) was analyzed in order to understand the effect on all-cause mortality. For descriptive statistics, continuous data are presented as mean and standard deviation when normally distributed and median and interquartile range in case of a non normal distribution. A P value of less than 0.05 was considered statistically significant. All analyses were performed using SPSS 19.0 software (SPSS Inc, Chicago, Ill).

RESULTS

Between November 2000 and December 2003, 178 patients were randomly assigned to open repair and 173 to endovascular repair. Baseline characteristics are presented in Table 1. The median follow-up was 6.4 years (range, 5.1 to 8.2 years). Information on

3


survival was available for all patients at five years postoperatively, for 79% at six years and for 53% at seven years. The following causes of death were identified: cardiovascular (n = 36; 30.5%), cancer (n = 36; 30.5%), pulmonary (n = 12; 10.2%), miscellaneous (n = 20; 16.9%), and unknown (n = 14; 11.9%). 6 In the univariable risk-factor analysis, the absence of statin therapy was significantly associated with poor survival (Fig 1).

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7

Pro

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Log-Rank p = 0.001 No Statin Statin

Number at RiskNo Statin 216 200 188 168 160 149 98 38Statin 135 131 127 124 115 113 60 24

Figure 1 Kaplan-Meier Estimates of Survival between patients with or without Statins. The standard error of both survival estimates does not exceed 10%, the maximum standard errors are 5.5% and 4.5% respectively at the end of both curves.

In the multivariable analysis, this factor maintained its association with higher mortality (Table 2); statin therapy was associated with better long-term survival after open or endovascular aneurysm repair (HR, 0.5; 95% confidence interval [CI], 0.3-0.8; P = 0.004). Several other factors were associated with reduced survival (Table 2):age >70 (HR, 3.4; 95% CI, 2.2-5.0; P < 0.001), cardiac disease (HR, 1.9; 95% CI, 1.3-2.8; P = .001), and moderate/severe tobacco use (HR, 1.7; 95% CI, 1.2-2.5;P = 0.004). Statin therapy was also associated with a reduced risk of cardiovascular deaths (P = 0.025; Fig 2). The influence of statin therapy on other causes of death (cancer, pulmonary, miscellaneous, and unknown) was not statistically significant. Gender, aneurysm size, the need for reintervention, pulmonary disease, renal disease, carotid artery disease, hypertension, diabetes mellitus, antiplatelet or anticoagulant agents, and b-blockers did not significantly influence overall survival.

32 | CHAPTER 3

Table 1 Baseline Characteristics

No Statin (N=216) Statin (N=135) p-value

Randomization Open 106 (49%) 72 (53%) 0.445

Endovascular 110 (51%) 63 (47%)

Gender Male 199 (92%) 123 (91%) 0.842

Female 17 (8%) 12 (9%)

Age 71.2 yrs (SD±6.8) 68.5 yrs (SD±6.2) < 0.001

Aneurysm size 60.2 mm (SD±8.5) 60.6 mm (SD±9.1) 0.676

B-blocking agents Without 126 (58%) 57 (42%) 0.004

With 90 (42%) 78 (58%)

Antiplatelet or anticoagulant therapy Without 60 (28%) 22 (16%) 0.014

With 156 (72%) 113 (84%)

SVS/ISCVS risk factors

DM No 198 (92%) 118 (87%) 0.395

Mild 15 (7%) 15 (11%)

Moderate 3 (1%) 2 (2%)

Severe 0 0

Tobacco No 78 (36%) 66 (49%) 0.048

Mild 47 (22%) 31 (23%)

Moderate 74 (34%) 32 (24%)

Severe 17 (8%) 6 (4%)

Hypertension No 105 (49%) 48 (36%) 0.040

Mild 71 (33%) 47 (35%)

Moderate 34 (16%) 36 (27%)

Severe 6 (3%) 4 (3%)

Carotid disease No 188 (87%) 111 (82%) 0.552

Mild 6 (3%) 6 (4%)

Moderate 15 (7%) 14 (10%)

Severe 7 (3%) 4 (3%)

Cardiac disease No 142 (66%) 54 (40%) < 0.001

Mild 63 (29%) 66 (49%)

Moderate 11 (5%) 15 (11%)

Severe 0 0

Renal disease No 196 (91%) 126 (93%) 0.560

Mild 19 (9%) 9 (7%)

Moderate 1 (1%) 0

Severe 0 0

Pulmonary disease No 155 (72%) 115 (85%) 0.034

Mild 45 (21%) 15 (11%)

Moderate 15 (7%) 5 (4%)

Severe 1 (1%) 0

3


Table 2 Factors influencing all-cause Mortality identified with a multivariable Cox-regression analysis. All the factors are adjusted for randomization group and mutually adjusted.

Hazard Ratio CI (95%) LB CI (95%) UB p-value

Age > 70 3.34 2.24 5.04 < 0.001

Gender 0.73 0.36 1.47 0.377

Aneurysm Size >70mm 1.54 .95 2.49 0.081

Reintervention 0.82 0.52 1.29 0.383

Cardiac Disease 1.94 1.33 2.81 0.001

Pulmonary Disease 1.06 0.69 1.62 0.792

Renal Disease 1.52 0.84 2.76 0.169

Carotid Disease 1.35 0.82 2.20 0.241

Hypertension 0.92 0.63 1.35 0.679

Diabetes 1.26 0.69 2.31 0.451

Tobacco 1.73 1.19 2.52 0.004

Statin 0.53 0.34 0.82 0.004

Antiplatelet/ Anticoagulant 1.33 0.82 2.16 0.250

B-blocker 0.89 0.60 1.33 0.577

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0.20

0.40

0.60

0.80

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0 1 2 3 4 5 6 7

Pro

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Log-Rank p = 0.025 No Statin Statin

Number at RiskNo Statin 216 200 188 168 160 149 98 38Statin 135 131 127 124 115 113 60 24

Figure 2 Kaplan-Meier Estimates of Cardiovascular Survival between patients with or without Statin use. The standard error of both survival estimates does not exceed 10%, the maximum standard errors are 4.3% and 3.6% respectively at the end of both curves.

34 | CHAPTER 3

DISCUSSION

This prospective study showed statin therapy to be independently associated with better long-term survival after open or endovascular aneurysm repair. The association between high levels of low-density lipoprotein (LDL) cholesterol and increasing cardiovascular disease and death has been studied extensively.28-30 LDL is a strong predictor for both mortality in patients with cardiovascular disease and coronary heart disease in patients without overt symptoms.28-30 Besides this effect, pleiotropic effects of statins, influencing endothelial function, inflammatory response, thrombus formation, and plaque stability, could affect perioperative and long-term outcomes after cardiovascular surgery as well.10-

24 Whatever the mechanism is, reducing LDL cholesterol and improving lipid profile in a cohort of AAA patients can be expected to attenuate the long-term cardiovascular disease and death. Previous studies have showed better perioperative outcomes of AAA repair with statin therapy.14,15,17,18,20 A reduction of mortality and perioperative cardiac events was achieved by decreasing death from cardiovascular causes or myocardial infarction in patients receiving lipid lowering therapy.14,15,17,18,20 Only a few studies showed a possible beneficial effect of statins on long-term survival after aneurysm repair, but these were all retrospective.10-12 Lipid-lowering therapy improved all-cause mortality in these studies. However, one study could only prove perioperative benefit and no long-term survival benefit after endovascular aneurysm repair in high cardiac risk patients.13 The long-term survival after elective aneurysm repair has been improved over time despite change in the case mix toward older patients with more comorbidities.25 Long-term survival after endovascular and open aneurysm repair are similar 6,7; thus, decreasing long-term mortality is not related to the introduction of endovascular aneurysm repair.25 Other factors influencing survival in our population are older age, cardiac disease, and tobacco use. Creating a Cox regression model allows correcting for these factors. Antiplatelet or anticoagulant agents and b-blockers are factors that have been associated with improved survival after cardiovascular surgery 17,26-28 and could influence long-term survival after aneurysm repair as well. Statin therapy remains an independent predictor after adjusting for these factors and increases long-term survival after AAA repair (open or endovascular). This trial started enrolling patients in 2000, at which time statins were not considered mandatory in cardiovascular risk management of AAA patients in The Netherlands. Our prospective trial with intensive follow-up offers the opportunity to analyze the determinants of long-term survival, without missing data or patients. However, this study was not designed to detect a difference in survival between patients with or without lipid lowering medication. While we adjusted for a number of potential confounding variables in the analyses, residual confounding cannot be excluded. A potential confounder in this study could be the level of primary care related to statin therapy. However, the antiplatelet/anticoagulant therapy or b-blockers

3


did not influence overall survival after aneurysm repair. An additional analysis, not included in this paper, showed no statistically significant association between other antihypertensive medication and crude survival. Another potential confounder is medication change over time, particularly initiation of statins in patients who were grouped in the no-statin group at inclusion or, conversely, discontinuation of statins or incomplete medication compliance in patients in the statin group. Both scenarios, however, would work in favor of our conclusion that statins have a beneficial effect on long-term survival because hypothetically, the effect-size of statins in these situations will be larger if the no-statin group only included patients who did not use statins at any time or if the statin group were composed of patients who were compliant the entire trial period. While we did not have information about the patients taking medication after surgery or compliance during follow-up, one could question whether the long-term survival benefit was due to taking statin at the time of the operation or during follow-up. In this trial, LDL or high-density lipoprotein cholesterol levels were not measured in order to determine the effectiveness of statin therapy. Hypothetically, if an unidentified subgroup patients exists in whom statin treatment is inadequate or ineffective, the overall effect could have been even greater by optimizing treatment in these patients. In addition, at the beginning of the trial, in the late nineties, the recommended dosage of lipid-lowering medication was not as high as current standards dictate, again suggesting that the survival benefit could have been larger if all patients would have received adequate dosages of statins. The specific formulation or dosage is not known for these patients; therefore, we cannot conclude which type of lipid-lowering therapy or dosage would beneficially influence our outcomes or decrease long-term survival. On the same note, patients who received statins for an indication (eg, high lipid levels or cardiac disease) are expected to have a higher a priori risk of events. This confounding by indication would again attenuate the true risk reduction. Even if the event rates would have been the same in the statin and no-statin groups in this trial, it could have reflected a risk reduction in the group that, by virtue of their previous elevated lipids, would have been entitled to have an (untreated) elevated risk. Whether crude survival and cardiovascular mortality is influenced by non-fatal cardiovascular events is unknown in this trial. This could clarify the beneficial effect of statin therapy. To identify the effect of statin therapy on long-term survival, a randomized trial should be performed. However, one could question whether this study would be ethically justified and even feasible, given the available evidence. Convergence of all-cause mortality or “catch-up” mortality between endovascular and open aneurysm repair in the DREAM and EVAR-1 trials is largely explained by higher rates of cardiovascular deaths in the endovascular repair groups during the first two years.5 Improving the cardiovascular risk profile with intensive vascular counselling and optimal cardio-protective medication can play a key role in sustaining the beneficial effect of endovascular aneurysm repair postoperatively.

36 | CHAPTER 3

CONCLUSION

Despite the limitations of a post-hoc analysis of a prospectively maintained trial, we conclude that statin therapy at the beginning of the trial is independently associated with improved long-term survival after open or endovascular aneurysm repair, while age above 70 years, cardiovascular disease, and moderate/severe tobacco use are associated with decreased long-term survival. The findings support the view that statin treatment is an essential element of risk management in patients undergoing aortic aneurysm treatment.

3


REFERENCES

1. Prinssen M, Verhoeven EL, Buth J, Cuypers PW, van Sambeek MR, Balm R, et al. Dutch Randomized Endovascular Aneurysm Management (DREAM) Trial Group. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2004;351:1607-18.

2. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG. EVAR trial participants. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet 2004;364:843-8.

3. Lederle FA, Freischlag JA, Kyriakides TC, Padberg FT Jr, Matsumura JS, Kohler TR, et al. Open Versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study Group. Outcomes following endovascular vs open repair of abdominal aortic aneurysm: a randomized trial. JAMA 2009;302:1535-42.

4. Blankensteijn JD, de Jong SE, Prinssen M, van der Ham AC, Buth J, van Sterkenburg SM, et al. Dutch Randomized Endovascular Aneurysm Management (DREAM) Trial Group. Two-year outcomes after conventional or endovascular repair of abdominal aortic aneurysms. N Engl J Med 2005;352:2398-405.

5. Brown LC, Thompson SG, Greenhalgh RM, Powell JT. Endovascular Aneurysm Repair trial participants. Incidence of cardiovascular events and death after open or endovascular repair of abdominal aortic aneurysm in the randomized EVAR trial 1. Br J Surg 2011;98:935-42.

6. De Bruin JL, Baas AF, Buth J, Prinssen M, Verhoeven EL, Cuypers PW, et al. DREAM Study Group. Long-term outcome of open or endovascular repair of abdominal aortic aneurysm. N Engl J Med 2010;362:1881-9.

7. United Kingdom EVAR Trial Investigators. Greenhalgh RM, Brown LC, Powell JT, Thompson SG, Epstein D, Sculpher MJ. Endovascular versus open repair of abdominal aortic aneurysm. N Engl J Med 2010;362:1863-71.

8. Eldrup N, Budtz-Lilly J, Laustsen J, Bibby BM, Paaske WP. Long-term incidence of myocardial infarct, stroke, and mortality in patients operated on for abdominal aortic aneurysms. J Vasc Surg 2012;55:311-7.

9. Twine CP, Williams IM. Systematic review and meta-analysis of the effects of statin therapy on abdominal aortic aneurysms. Br J Surg 2011;98:346-53.

10. Leurs LJ, Visser P, Laheij RJ, Buth J, Harris PL, Blankensteijn JD. Statin use is associated with reduced all-cause mortality after endovascular abdominal aortic aneurysm repair. Vascular 2006;14:1-8.

11. Kertai MD, Boersma E, Westerhout CM, van Domburg R, Klein J, Bax JJ, et al. Association between long-term statin use and mortality after successful abdominal aortic aneurysm surgery. Am J Med 2004;116:96-103.

12. Diehm N, Becker G, Katzen B, Benenati J, Kovacs M, Dick F. Statins are associated with decreased mortality in abdominal, but not in thoracic aortic aneurysm patients undergoing endovascular repair: propensity score-adjusted analysis. Vasa 2008;37:241-9.

13. Schouten O, Lever TM, Welten GM, Winkel TA, Dols LF, Bax JJ, et al. Long-term cardiac outcome in high-risk patients undergoing elective endovascular or open infrarenal abdominal aortic aneurysm repair. Eur J Vasc Endovasc Surg 2008;36:646-52.

14. Poldermans D, Bax JJ, Kertai MD, Krenning B, Westerhout CM, Schinkel AF, et al. Statins are associated with a reduced incidence of perioperative mortality in patients undergoing major noncardiac vascular surgery. Circulation 2003;107:1848-51.

38 | CHAPTER 3

15. Durazzo AE, Machado FS, Ikeoka DT, De Bernoche C, Monachini MC, Puech-Leão P, et al. Reduction in cardiovascular events after vascular surgery with atorvastatin: a randomized trial. J Vasc Surg 2004;39:967-75.

16. O’Neil-Callahan K, Katsimaglis G, Tepper MR, Ryan J, Mosby C, Ioannidis JP, et al. Statins decrease perioperative cardiac complications in patients undergoing noncardiac vascular surgery: the Statins for Risk Reduction in Surgery (StaRRS) study. J Am Coll Cardiol 2005;45: 336-42.

17. Kertai MD, Boersma E, Westerhout CM, Klein J, Van Urk H, Bax JJ, et al. A combination of statins and beta-blockers is independently associated with a reduction in the incidence of perioperative mortality and nonfatal myocardial infarction in patients undergoing abdominal aortic aneurysm surgery. Eur J Vasc Endovasc Surg 2004;28:343-52.

18. Schouten O, Boersma E, Hoeks SE, Benner R, van Urk H, van Sambeek MR, et al. Dutch Echocardiographic Cardiac Risk Evaluation Applying Stress Echocardiography Study Group. Fluvastatin and perioperative events in patients undergoing vascular surgery. N Engl J Med 2009;361:980-9.

19. Le Manach Y, Ibanez Esteves C, Bertrand M, Goarin JP, Fléron MH, Coriat P, et al. Impact of preoperative statin therapy on adverse postoperative outcomes in patients undergoing vascular surgery. Anesthesiology 2011;114:98-104.

20. McNally MM, Agle SC, Parker FM, Bogey WM, Powell CS, Stoner MC. Preoperative statin therapy is associated with improved outcomes and resource utilization in patients undergoing aortic aneurysm repair. J Vasc Surg 2010;51:1390-6.

21. Prinssen M, Buskens E, Blankensteijn JD. The Dutch Randomised Endovascular Aneurysm Management (DREAM) trial. Background, design and methods. J Cardiovasc Surg (Torino) 2002;43: 379-84.

22. Rosenson RS, Tangney CC. Beneficial effects of statins. Lancet 1996;348:1583.23. Rosenson RS, Tangney CC. Antiatherothrombotic properties of statins: implications for

cardiovascular event reduction. JAMA 1998;279: 1643-50.24. Rosenson RS, Tangney CC, Casey LC. Inhibition of proinflammatory cytokine production by

pravastatin. Lancet 1999;353:983-4.25. Mani K, Björck M, Lundkvist J, Wanhainen A. Improved long-term survival after abdominal

aortic aneurysm repair. Circulation 2009;120: 201-11.26. Pignone M, Mulrow C. Antiplatelet therapy and atherosclerotic events. Risks and patients’

values need to be included in decision about aspirin for prevention of coronary heart disease. BMJ 2002;324:917.

27. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ 2002;324: 71-86.

28. Pekkanen J, Linn S, Heiss G, Suchindran CM, Leon A, Rifkind BM, et al. Ten-year mortality from cardiovascular disease in relation to cholesterol level among men with and without preexisting cardiovascular disease. N Engl J Med 1990;322:1700-7.

29. Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837-47.

30. Grundy SM. Small LDL, atherogenic dyslipidemia, and the metabolic syndrome. Circulation 1997;95:1-4.

Predicting reinterventions after open and endovascular aneurysm repair: The St George’s vascular institute score

Chapter 4

4

PREDICTING REINTERVENTIONS | 41

BACKGROUND

The Achilles’ heel of endovascular aneurysm repair (EVAR) remains the durability of aneurysm sac exclusion. 1-4 Endoleak, migration or even rupture may follow EVAR and result in a higher reported rate of reintervention than is seen after open abdominal aortic aneurysm (AAA) repair.1-4 Endograft surveillance is considered mandatory after EVAR, but there is considerable uncertainty in Europe and in the United Kingdom (UK) regarding when and how surveillance should be performed.5,6 The initial U.S. Food and Drug Administration recommendations regarding instructions for use included computed tomography (CT) surveillance after implantation; imaging should be performed at one month, six months, and then yearly.7 The Society for Vascular Surgery guidelines published in 2009 by Chaikoff et al 8 recommend contrast-enhanced CT imaging one and 12 months after the initial aneurysm repair. Should CT imaging at one month after EVAR reveal an endoleak or findings of concern, a CT at six months should be added to further evaluate the aneurysm exclusion. Color duplex ultrasound imaging may be a defensible alternative to CT scanning for postoperative surveillance, provided that neither an endoleak nor aneurysm enlargement is identified on CT during the initial year after EVAR. The risk of reintervention is known to vary for different patients undergoing EVAR, suggesting that surveillance might be targeted to those at greatest risk. For example, reintervention is more likely for patients treated outside the instructions for use of an endovascular device,4 whereas several anatomic features have been associated in isolation with specific complications requiring reintervention.4,9-13 To identify patients at risk of endoleak, migration, or other complications requiring reintervention after EVAR, a scoring system, the St George’s Vascular Institute (SGVI) risk score,10 was developed in two UK centers.This comprised the iliac and aortic diameter (exp [(0.03675 x maximum aortic diameter) (0.05009 x largest common iliac diameter)]), and was created to subdivide patients into low-risk (<3.76571) and high-risk categories (≥3.76571).10 However, the external validity of this UK-based scoring system is restricted to testing its value in one registry with midterm follow-up. AAA-related reintervention is infrequent after open repair, but laparotomy-related interventions do occur (±10%)14,15 and seem to occur more frequently after aneurysm repair than after surgery for aortic-occlusive disease. 16 Although an underlying connective tissue defect has not been identified to link AAAs with abdominal wall healing,17 the association between abdominal wall hernias, incisional hernias, and AAAs is well known.15-19 Whether the extensiveness of aneurysmal disease, including iliac aneurysm disease and larger aortic aneurysms, is related to more reinterventions after conventional AAA repair isunknown. However, identification of a link between preoperative AAA morphology and the long-term reintervention rate after open repair could help in identifying patients

42 | CHAPTER 4

at risk of an incisional hernia, who could benefit from clear postoperative instructions and possibly intensified follow-up. The study aimed to identify patients at risk for a reintervention after open repair or EVAR, through a post hoc application of the SGVI score to data from the Dutch Randomised Endovascular Aneurysm Management (DREAM) randomized controlled trial of open AAA repair vs EVAR for infrarenal AAA. The study further aimed to provide external validation for the SGVI score by using multicenter randomized controlled trial data rather than single-center observational data or registry data.20

METHODS

A post hoc analysis of the DREAM trial was performed. The design and methods of the trial have been described in detail elsewhere.21 In summary, 351 patients referred to vascular surgery departments at 26 centers in the Netherlands and four centers in Belgium, with an AAA of ≥ five cm in diameter and considered suitable candidates for both techniques, were randomly assigned to open repair or EVAR after giving written informed consent. The trial was conducted according to the Declaration of Helsinki, and the Institutional Review Board of each participating hospital approved the protocol. For this analysis, data acquisition was stopped on February 1, 2009. Patients who had declined further participation at two years or who were initially lost to follow-up were contacted directly or through their relatives or physicians. All medical records at the participating hospitals were scrutinized for information about reinterventions and causes of death. Follow-up visits at the inception of the trial were scheduled at 30 days and at six, 12, 18, and 24months after the initial intervention. After the first two years of close follow-up, patients received a questionnaire every six months requesting information about visits to physicians and all hospital admissions. Follow-up for patients in the EVAR group included a yearly follow-up visit and a CT scan. Patients in the open repair group were instructed to see their physicians annually but were not actively recruited for follow-up visits three and four years after surgery. All patients were contacted by telephone five years postoperatively and were invited for a follow-up visit with a CT scan. Medical records were used to confirm the information that patients had provided. All aneurysm-related reinterventions and incisional hernia repairs were regarded to be a reintervention. The SGVI score was used to estimate the risk of reintervention after AAA repair. Aneurysm morphologic assessment was performed using the European Collaborators on Stent-Graft Techniques for Abdominal Aortic Aneurysm Repair (EUROSTAR) classification.22 As noted above, the SGVI score formula uses the iliac and aortic diameter to calculate the score, with which patients are subdivided into low-risk (<3.76571) and high-risk categories (≥3.76571).10 Demographics and subsequent secondary reintervention rates

4


in patients identified as being high-risk by the SGVI score were compared with low-risk patients.10 To compare reintervention rates in these groups, outcomes were estimated using Kaplan-Meier functions and compared using the log-rank test. For descriptive statistics, continuous data is presented as mean ± standard deviation when normally distributed and median (interquartile range) in case of a non-normal distribution. A P value of <.05 was considered statistically significant. All analyses were performed using SPSS 20.0 software (IBM Corp, Armonk, NY).

RESULTS

Between November 2000 and December 2003, 178 patients were randomly assigned to open repair and 173 to EVAR. The median follow-up was 6.4 years (range, 5.1-8.2 years). Information on survival and reinterventions was available for all patients at five years postoperatively, for 79% at six years, and for 53% at seven years. Preoperative aneurysm and iliac diameter were available in, respectively, 351 (100%) and 334 (95.2%) patients. Open aneurysm repair was performed in 173 patients and EVAR in 171 patients, based on an on-treatment analysis. Because 17 patients had incomplete morphologic data, 327 patients (157 open repair and 170 EVAR) were available for analysis. Anatomic characteristics and baseline characteristics of low-risk and high-risk patients (SGVI score) are listed in Table 1. Most patients were treated with a Zenith (Cook Medical, Bloomington, Ind), Talent (Medtronic, Minneapolis, Minn), or Excluder (W. L. Gore & Associates, Flagstaff, Ariz) endovascular stent graft. During follow-up, one or more reinterventions were performed in 48 patients in the EVAR randomization group and in 30 patients in the open repair randomization group. The interventions are reported in Table 2.

When considering open repair and EVAR together, the 20 patients in the high-risk group were at a significantly higher risk of secondary intervention than the 307 patients with a low SGVI score (hazard ratio [HR], 3.82; 95% confidence interval [CI], 2.05-7.11; P < 0.001; Fig 1). Patients in the EVAR cohort identified using preoperative morphologic data as being high-risk using the SGVI score underwent a larger number of reinterventions than those patients identified as low risk (HR, 4.06; 95% CI, 1.93-8.51; P < 0.001; Fig 2A). Similarly, the high-risk patients in the open repair cohort underwent a larger number of reinterventions than the low-risk patients (HR, 3.41; 95% CI, 1.02-11.4; P = 0.033; Fig 2B).

44 | CHAPTER 4

Table 1 Anatomical & Baseline Characteristics of all patients completed their aneurysm repair and known iliac diameter.

Low Risk Group(SGVI<3.76571)

N = 307

High Risk Group(SGVI ≥3.76571)

N = 20p-value

Age (SD) 69.9 (±6.7) 73.1 (±6.3) 0.037

Male 281 (91.5%) 19 (95.0%) 1.000

Aneurysm Size/max diameter (mm)

Mean(SD) 59.1 (±7.0) 82.4 (±6.6) <0.001

Median 58.0 (54.0 – 63.3) 80.0 (78.8 - 85.0) <0.001

Iliac Diameter (mm)

Mean(SD) 14.1 (±3.0) 18.1 (±3.8) <0.001

Median 13.7 (12.0 – 16.0) 18.0 (16.8 – 19.3) <0.001

Neck Diameter (mm)

Mean(SD) 23.8 (±3.3) 26.5 (±3.1) <0.001

Median 23.1 (21.7 – 26.0) 25.5 (24.8 – 29.0) <0.001

Neck Length (mm)

Mean(SD) 24.9 (±11.7) 25.1 (±8.2) 0.960

Median 21.0 (17.0 – 30.0) 24.5 (20.0 – 30.0) 0.471

Type Morphology

Type A 24 (7.8%) 1 (5.0%) <0.001

Type B 199 (64.8%) 7 (35.0%)

Type C 35 (11.4%) 1 (5.0%)

Type D 21 (6.8%) 6 (30.0%)

Type E 28 (9.1%) 5 (25.0%)Mild, Moderate Severe SVS/ISCVS FACTORS (N - %)

Diabetes mellitus 30 (9.8%) 3 (15.0%) 0.439

Tobacco use 186 (60.6%) 10 (50.0%) 0.357

Hypertension 172 (56.0%) 12 (60.0%) 0.819

Dyslipedemia 149 (48.5%) 10 (50.0%) 1.000

Carotid artery disease 44 (14.3%) 4 (20.0%) 0.512

Cardiac disease 129 (42.0%) 13 (65.0%) 0.061

Renal disease 26 (8.5%) 0 (0%) 0.386

Pulmonary disease 71 (23.1%) 4 (20.0%) 1.000

4


Table 2 Indication for secondary intervention (randomization group)

Endovascular Repair Open Repair Total

All secondary interventions 48* 30** 78

Local or wound related interventions(including incisional hernia)

3 15 18

Graft-related interventions 42 6 48

Hematoma evacuation or bleeding 2 5 7

Miscellaneous 1 4 5

* 22 of these secondary interventions were emergency interventions ** 16 of these re-interventions were emergency interventions

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7

Free

dom

from

Re-

inte

rven

tion


Log-Rank p < 0.001 High Risk Low Risk

Number at RiskLow Risk 307 260 241 224 207 192 120 46High Risk 20 13 12 11 11 6 1 0

Figure 1 Kaplan-Meier estimates of freedom from re-intervention in the high- risk and low-risk patient category group according to the SGVI score for both open and endovascular aneurysm repair. Log–rank test p < 0.001.

46 | CHAPTER 4

A

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7

Free

dom

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Log-Rank p < 0.001 High Risk Low Risk


B

0.00

0.20

0.40

0.60

0.80

1.00

0 1 2 3 4 5 6 7

Free

dom

from

Re-

inte

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Log-Rank p = 0.033 High Risk Low Risk


Figure 2 Kaplan-Meier estimates of freedom from re-intervention in the high- risk and low-risk patient category group according to the SGVI score for endovascular (2A) and open (2B) aneurysm repair (on-treatment analysis). Log–rank test p < 0.001 and p = 0.033 respectively.

4


DISCUSSION

This post hoc analysis of patients in a randomized trial showed a clear association between the SGVI score and reintervention risk. The SGVI score was predictive of reintervention for EVAR and open AAA repair. This study serves as an external and international validation of the SGVI risk score and demonstrates that it can reproducibly be used to predict endograft complications after surgery. The association between several morphologic features of the aneurysm and risk of a secondary intervention is established.4,9-13 The SGVI scoring system is comprehensive and easy to use and predicts reintervention risk by using preoperative measurements.10 The Endovascular vs Open Abdominal Aortic Aneurysm Repair (EVAR)-1, DREAM, and Open vs Endovascular Repair trials have shown that graft-related complications and secondary intervention are common after EVAR,1-3 especially in patients with a large aneurysm.12 Several studies have shown that patients with larger aneurysms are at greater risk of significant complications after endovascular repair.23 The EVAR-1 and EUROSTAR authors have reported that patients with larger AAA and iliac diameter were at greater risk of reintervention, and the EUROSTAR investigators previously proposed that these patients might need more intensive surveillance postoperatively.12,24 The SGVI score incorporates aneurysm and iliac diameter and formalizes their relationship with reintervention in a risk score that is easy to use for practicing clinicians. Relatively few patients (20 [6.1%]) were categorized as high risk, and practice has evolved since DREAM in terms of endograft technology, operator experience, and approaches to reintervention. However, recent registry data demonstrates that despite evolutions in practice, reinterventions remain a concern after EVAR and can be predicted by the SGVI score.20 The present external validation study also demonstrated that the SGVI score was of use in predicting the risk of reintervention after open repair. This holds face validity, because patients with larger aneurysms may also have more complex aneurysm anatomy and require more extensive and complex open aneurysm repair. Supporting this are previous findings that patients undergoing AAA repair for acute symptomatic aneurysms have improved survival when there is simple anatomy or suitability for EVAR.25 This study has several limitations. One of the limitations is the follow-up in the open repair group after the initial two years of our trial, because patients in the open repair group did not undergo CT in the third and fourth years after their aneurysm repair. Only one-fourth of the open repair patients underwent CT at five years compared with most of the patients in the EVAR group. Ascertainment bias could have contributed to discovering more graft-related problems in the EVAR group. Conversely, although subjecting patients to intensive follow-up after open repair is not common practice, this may have led to an artificially high rate of reinterventions after open repair. Secondly, although short and angulated aneurysm necks were excluded at the inception of our

48 | CHAPTER 4

trial, these morphologic features will influence EVAR results in current practice and, therefore, will influence outcomes if patients are treated outside the instructions for use. Thirdly, we did not analyze the influence of body mass index on our results with regards to incisional hernia repair, which is a well-known risk factor. Finally, the SGVI score was developed in patients after EVAR predicting aortic complications; however, it seems to predict non-aortic complications in patients after open repair as well. A confounding factor could contribute to this finding, and these results need to be carefully weighed. This study demonstrates that stratifying the risks of major complications before open and EVAR is possible by using a simple scoring system and two routinely recorded morphologic features (aortic and iliac diameter). The SGVI score might be used to better inform patient selection or in the preoperative consent process. Patients in the highest-risk category could be advised of the risks inherent in both open repair and EVAR before the procedure. Furthermore, the SGVI score might facilitate the risk adjustment of long-term performance data at the institutional or surgeon level or allow more informed comparison of turndown rates for elective AAA repair. One alternative for the SGVI score arguably lies in enabling the stratification of surveillance imaging after EVAR; for instance, intensified surveillance for patients with adverse morphologic features. Prolonged endograft surveillance is currently considered mandatory after EVAR, according to the European Society for Vascular Surgery guidelines.5 However, surveillance protocols after EVAR represent a major research problem.26 Furthermore, serial CT scans are used in many institutions, exposing patients to cumulative irradiation and nephrotoxic contrast agents.6 There is widespread variation in the protocols used for endograft surveillance, reflecting a lack of evidence to inform the frequency and modality of imaging.6,26,27 Modern surveillance protocols are inefficient and do not identify most of the complications after EVAR,28-31 which more usually present due to the development of alarming symptoms between apparently normal surveillance scans.32 Surprisingly, the SGVI score predicted reinterventions after conventional repair as well. Although the largest proportion of these reinterventions is related to the laparotomy, some of the patients also underwent aneurysm related surgery.2,3,14 Laparotomy-related interventions seem to occur more frequently after aneurysm repair than after surgery for aortic occlusive disease.16 The authors of a recent review could not identify sufficient data to support an underlying connective tissue defect affecting both the abdominal and aortic wall.17 However, the association between abdominal wall hernias or incisional hernias and AAA, is well known.15-19 During our study, the extensiveness of aneurysmal disease, including iliac aneurysm disease and larger aortic aneurysms, is related to more reinterventions after conventional AAA repair. Further research should address the hypothesis of whether risk-stratified surveillance after EVAR and intensifying follow-up for patients at risk after conventional repair can fulfil the dual aims of improving the cost-effectiveness of the procedure without jeopardizing the long-term safety.

4


CONCLUSION

The SGVI score was validated using the prospectively collected data from the DREAM trial. This adds to the evidence that the SGVI score is a useful tool to predict reintervention risk in patients after open repair and EVAR during this trial. More extensive aneurysmal disease seems to be related with higher reintervention rates after conventional aneurysm repair. Further investigation is needed to identify whether these high-risk patients would benefit from intensified follow-up, not only in the EVAR group but also after conventional repair.

50 | CHAPTER 4

REFERENCES

1. Greenhalgh RM, Brown LC, Powell JT, Thompson SG, Epstein D, Sculpher MJ. Endovascular versus open repair of abdominal aortic aneurysm. N Engl J Med 2010;362:1863-71.

2. De Bruin JL, Baas AF, Buth J, Prinssen M, Verhoeven EL, Cuypers PW, et al. Long-term outcome of open or endovascular repair of abdominal aortic aneurysm. N Engl J Med 2010;362:1881-9.

3. Lederle FA, Freischlag JA, Kyriakides TC, Matsumura JS, Padberg FT Jr, Kohler TR, et al; OVER Veterans Affairs Cooperative Study Group. Long-term comparison of endovascular and open repair of abdominal aortic aneurysm. N Engl J Med 2012;367:1988-97.

4. Schanzer A, Greenberg RK, Hevelone N, Robinson WP, Eslami MH, Goldberg RJ, et al. Predictors of abdominal aortic aneurysm sac enlargement after endovascular repair. Circulation 2011;123:2848-55.

5. Moll FL, Powell JT, Fraedrich G, Verzini F, Haulon S, Waltham M, et al; European Society for Vascular Surgery. Management of abdominal aortic aneurysms clinical practice guidelines of the European society for vascular surgery. Eur J Vasc Endovasc Surg 2011;41(Suppl 1):S1-58.

6. Karthikesalingam A, Page AA, Pettengell C, Hinchliffe RJ, Loftus IM, Thompson MM, et al. Heterogeneity in surveillance after endovascular aneurysm repair in the UK. Eur J Vasc Endovasc Surg 2011;42: 585-90.

7. Sapirstein W, Chandeysson P, Wentz C. The Food and Drug Administration approval of endovascular grafts for abdominal aortic aneurysm: an 18-month retrospective. J Vasc Surg 2001;34:180-3.

8. Chaikof EL, Brewster DC, Dalman RL, Makaroun MS, Illig KA, Sicard GA, et al. SVS practice guidelines for the care of patients with an abdominal aortic aneurysm: executive summary. J Vasc Surg 2009;50: 880-96.

9. Johnson PG, Chipman CR, Ahanchi SS, Kim JH, Dexter DJ, Panneton JM. A case-matched validation study of anatomic severity grade score in predicting reinterventions after endovascular aortic aneurysm repair. J Vasc Surg 2013;58:582-8.

10. Karthikesalingam A, Holt PJ, Vidal-Diez A, Choke EC, Patterson BO, Thompson LJ, et al. Predicting aortic complications after endovascular aneurysm repair. Br J Surg 2013;100:1302-11.

11. Holt PJ, Karthikesalingam A, Patterson BO, Ghatwary T, Hinchliffe RJ, Loftus IM, et al. Aortic rupture and sac expansion after endovascular repair of abdominal aortic aneurysm. Br J Surg 2012;99: 1657-64.

12. Brown LC, Greenhalgh RM, Powell JT, Thompson SG; EVAR Trial Participants. Use of baseline factors to predict complications and reinterventions after endovascular repair of abdominal aortic aneurysm. Br J Surg 2010;97:1207-17.

13. Wyss TR, Dick F, Brown LC, Greenhalgh RM. The influence of thrombus, calcification, angulation, and tortuosity of attachment sites on the time to the first graft-related complication after endovascular aneurysm repair. J Vasc Surg 2011;54:965-71.

14. Schermerhorn ML, O’Malley AJ, Jhaveri A, Cotterill P, Pomposelli F, Landon BE. Endovascular vs. open repair of abdominal aortic aneurysms in the Medicare population. N Engl J Med 2008;358:464-74.

15. Alnassar S, Bawahab M, Abdoh A, Guzman R, Al Tuwaijiri T, Louridas G. Incisional hernia postrepair of abdominal aortic occlusive and aneurysmal disease: five-year incidence. Vascular 2012;20:273-7.

4


16. Henriksen NA, Helgstrand F, Vogt KC, Jorgensen LN, Bisgaard T; Danish Hernia Database; Danish Vascular Registry. Risk factors for incisional hernia repair after aortic reconstructive surgery in a nationwide study. J Vasc Surg 2013;57:1524-30. 1530.e1-3.

17. Antoniou GA, Georgiadis GS, Antoniou SA, Granderath FA, Giannoukas AD, Lazarides MK. Abdominal aortic aneurysm and abdominal wall hernia as manifestations of a connective tissue disorder. J Vasc Surg 2011;54:1175-81.

18. Liapis CD, Dimitroulis DA, Kakisis JD, Nikolaou AN, Skandalakis P, Daskalopoulos M, et al. Incidence of incisional hernias in patients operated on for aneurysm or occlusive disease. Am Surg 2004;70:550-2.

19. Antoniou GA, Giannoukas AD, Georgiadis GS, Antoniou SA, Simopoulos C, Prassopoulos P, et al. Increased prevalence of abdominal aortic aneurysm in patients undergoing inguinal hernia repair compared with patients without hernia receiving aneurysm screening. J Vasc Surg 2011;53:1184-8.

20. Karthikesalingam A, Vidal-Diez A, De Bruin JL, Thompson MM, Hinchliffe RJ, Loftus IM, et al. International validation of a risk score for complications and reinterventions after endovascular aneurysm repair. Br J Surg 2015;102:509-15.

21. Prinssen M, Buskens E, Blankensteijn JD. The Dutch Randomised Endovascular Aneurysm Management (DREAM) trial. Background, design and methods. J Cardiovasc Surg (Torino) 2002;43:379-84.

22. Harris PL, Buth J, Mialhe C, Myhre HO, Norgren L. The need for clinical trials of endovascular abdominal aortic aneurysm stent-graft repair: The EUROSTAR Project. EUROpean collaborators on Stentgraft Techniques for abdominal aortic Aneurysm Repair. J Endovasc Surg 1997;4:72-7; discussion: 478-9.

23. Keith CJ Jr, Passman MA, Gaffud MJ, Novak Z, Pearce BJ, Matthews TC, et al. Comparison of outcomes following endovascular repair of abdominal aortic aneurysms based on size threshold. J Vasc Surg 2013;58:1458-66.

24. Peppelenbosch N, Buth J, Harris PL, van Marrewijk C, Fransen G; EUROSTAR Collaborators. Diameter of abdominal aortic aneurysm and outcome of endovascular aneurysm repair: does size matter? A report from EUROSTAR. J Vasc Surg 2004;39:288-97.

25. Perrott S, Puckridge PJ, Foreman RK, Russell DA, Spark JI. Anatomical suitability for endovascular AAA repair may affect outcomes following rupture. Eur J Vasc Endovasc Surg 2010;40:186-90.

26. National Institute for Health and Care Excellence. NICE guidelines: endovascular stent-grafts for the treatment of abdominal aortic aneurysms. Available at: https://www.nice.org.uk/guidance/TA167. Accessed September 21, 2015.

27. Patel A, Edwards R, Chandramohan S. Surveillance of patients post endovascular abdominal aortic aneurysm repair (EVAR). A web based survey of practice in the UK. Clin Radiol 2013;68:580-7.

28. Karthikesalingam A, Holt PJ, Hinchliffe RJ, Nordon IM, Loftus IM, Thompson MM. Risk of reintervention after endovascular aortic aneurysm repair. Br J Surg 2010;97:657-63.

29. Uthoff H, Peña C, Katzen BT, Gandhi R, West J, Benenati JF, et al. Current clinical practice in postoperative endovascular aneurysm repair imaging surveillance. J Vasc Interv Radiol 2012;23:1152-9.e6.

30. Dias NV, Riva L, Ivancev K, Resch T, Sonesson B, Malina M. Is there a benefit of frequent CT follow-up after EVAR? Eur J Vasc Endovasc Surg 2009;37:425-30.

52 | CHAPTER 4

31. Chisci E, Setacci F, Iacoponi F, de Donato G, Cappelli A, Setacci C. Surveillance imaging modality does not affect detection rate of asymptomatic secondary interventions following EVAR. Eur J Vasc Endovasc Surg 2012;43:276-81.

32. Black SA, Carrell TW, Bell RE, Waltham M, Reidy J, Taylor PR. Long term surveillance with computed tomography after endovascular aneurysm repair may not be justified. Br J Surg 2009;96:1280-3.

Residual infrarenal aortic neck following endovascular and open aneurysm repair

Chapter 5

5

AORTIC NECK | 55

BACKGROUND

While the effectiveness of open (OR) and endovascular aortic abdominal aneurysm (EVAR) repair can be jeopardised by postoperative changes of the residual infrarenal neck,1-5 the long-term clinical significance of aortic neck dilatation is still subject to debate.2,3,6 In theory, endovascular aneurysm repair (EVAR) allows an (endovascular) anastomosis closer to the renal arteries than after open repair because no infrarenal clamp is required. This leaves a shorter untreated infrarenal segment in situ (or none at all) after EVAR as opposed to a residual (clamped) segment after open repair. It has been demonstrated that the infrarenal aorta can dilate after aneurysm repair. This accounts for both the untreated residual infrarenal segment after open repair7-16 and the endovascular infrarenal sealing zone after EVAR.1,4,6,17-21 In particular, when choosing between open and EVAR in relatively young and low-risk patients, durability of EVAR is of utmost importance. It is currently unknown how much residual infrarenal aorta is left in situ after open repair in patients who are suitable for EVAR. The objective of this study was to determine the length of the residual untreated infrarenal segment after EVAR and OR in a randomised trial.

METHODS

In the Dutch Randomised Endovascular Aneurysm Management (DREAM) trial, patients suitable for both treatments are randomly allocated to EVAR or OR. The study design has been described elsewhere.22 In brief, patients referred to surgery clinics at 24 centres in the Netherlands and four centres in Belgium, who had received a diagnosis of an abdominal aortic aneurysm (AAA) of at least five cm in diameter and who were considered suitable candidates for both techniques, were randomly assigned to undergo OR or EVAR after giving written informed consent. A patient’s suitability for EVAR was primarily determined by means of endograft-dependent anatomical criteria. A patient’s suitability for open repair was determined by an internist or a cardiologist. Patients who needed to undergo emergency aneurysm repair were excluded from the study, as were patients with inflammatory aneurysms, anatomical variations, connective tissue disease, a history of organ transplantations or a life expectancy of less than two years. The study was performed according to the principles of the Declaration of Helsinki, and the institutional board of each participating hospital approved the protocol. The exposure and aneurysm repair technique used for open repair was at the surgeon’s discretion. The intended position of the endovascular or conventional graft was directly beneath the lowest renal artery. Computed tomography (CT) scans were obtained within six months after surgery. A standardised protocol was applied to assess

56 | CHAPTER 5

the quality of the CT images: for instance, the CT-table position in mm was required. All CT images, on conventional film or in digital format, were reviewed to measure the residual infrarenal neck. Intra-observer variability tends to be smaller than inter-observer variability.23 Therefore, all data were measured by one physician. In case the level of the anastomosis was not obvious, another physician obtained a second measurement, blinded to the first measurement, to arrive at a mean value. Both physicians were well experienced in measuring aortic dimensions from computed tomography angiography (CTA) scans in EVAR patients. The distance between the caudal renal artery and the proximal anastomosis was measured using axial CT slices. Subsequently, the obtained lengths of the residual infrarenal aorta were categorised into six classes (0-5, 6-10, 11-15, 16-20,21-25, >25 mm). Immediately after the operation, surgeons were asked to enter in the case record form whether the level of their anastomosis after open repair was within or beyond 10mm of the caudal renal artery. All surgeons were well experienced in performing vascular and endovascular surgery; however, their self-assessment skills were unknown. Differences between treatment groups were evaluated with the use of the Mann-Whitney U test for continuous variables and Fisher’s exact test for proportions. All reported p-values are two sided and are not adjusted for multiple testing.

RESULTS

Between November 2000 and December 2003, 351 patients were randomly assigned to undergo either OR or EVAR. Of the 351 randomised patients, six patients did not undergo surgery (four declined and two died preoperatively). During the first part of the trial, 10 patients died in the hospital after surgery. A total of 165 patients were discharged after open AAA repair (OR) and 169 after endovascular AAA repair (EVAR). Seven patients died within the first year, while four patients had renal dysfunction and did not undergo CT within the first six months after aneurysm repair. One CT was not performed with intravenously contrast. Two CTs lacked slice thickness. One CT was damaged, and three patients did not receive CT for unknown reasons. Therefore, CT images were available and suitable for analysis in 156 of 165 (95%) OR patients and in 160 of 169 (95%) EVAR patients. There were no differences in baseline characteristics (age, gender and mean aneurysm size) between EVAR and OR (Table 1). The SVS/ISCVS risk factor score did not differ significantly except for tobacco use. Fig. 1 shows the lengths of the infrarenal segment after OR and EVAR. The median distance from the caudal renal artery to the proximal anastomosis was 24 mm (interquartile (IQ) range = 16-30 mm) in the OR group and 0 mm (IQ range = 0-6 mm) in the EVAR group (p < 0.0001, Mann-Whitney).

5

AORTIC NECK | 57

Table 1 Baseline Characteristics

OR (156) EVAR (160) p-value

Age-yr 69 ± 6.6 70 ± 6.7 0.13

Male sex –no. (%) 141 (90%) 149 (93%) 0.38

SVS/ISCVS-risk factor score (% moderate or severe)

Diabetes Mellitus 16 (10%) 15 (9%) 0.83

Tobacco Use 80 (52%) 102 (64%) 0.02

Hypertension 85 (54%) 93 (58%) 0.51

Cardiac Disease 69 (44%) 65 (41%) 0.75

Renal Disease 12 (8%) 12 (8%) 0.59

Maximum diameter-mm (Mean±SD) 60.3 ± 8.6 60.6 ± 8.9 0.95

0

10

20

30

40

50

60

Endovascular Repair Open Repair

Dist

ance

to re

nal a

rter

y (m

m)

Figure 1 Median distance from caudal renal artery to proximal anastomosis of the graft displayed with boxplots. Boxes are displayed as interquartile ranges and error bars are minimum and maximum values.

The distances as categorised into six length classes are depicted in Table 2. In 140 of 156 (90%) patients, at least one cm of untreated infrarenal neck persisted after OR and in 17 of 160 (10%) after EVAR. In 84 of the 156 patients (54%), the surgeon had indicated the proximal anastomosis was within 10mm of the caudal renal artery. Only five surgeons (6%) were accurate in this respect. Of the 94% surgeons whose estimation had been incorrect, the median distance of their anastomosis to the renal artery was 23 mm (IQ range 16-28 mm). Of the 72 surgeons who had indicated that their proximal

58 | CHAPTER 5

anastomosis was not within 10 mm of the caudal renal artery, 69 (96%) were correct. The median distance of their anastomosis to the renal artery was 30 mm (IQ range 20-36). In the OR group, about one-fourth of the patients at risk five years after randomisation had a CT scan; of these 34 patients, two (5.8%) had a para-anastomotic aneurysm.

Table 2 Length of the residual infrarenal aorta

Categories according to distances(mm)

OR EVAR

N N

0 - 5 6 (4%) 116 (73%)

6 - 10 10 (6%) 27 (17%)

11- 15 18 (12%) 10 (6%)

16- 20 28 (18%) 3 (2%)

21- 25 37 (24%) 4 (3%)

>25 57 (37%) 0

Total 156 160

DISCUSSION

This is the first study to compare the length of the remaining, untreated infrarenal neck after EVAR and OR in a randomized controlled trial. This study demonstrates that after OR, a longer segment of infrarenal neck is left untreated than after EVAR. This length is underestimated by most surgeons and could have a negative impact on the long-term durability of OR. Conversely, endoleak and endograft migration can occur after EVAR particularly with continuing dilatation of the infrarenal aortic neck.1,4,5,17,20 Both aorto-enteric fistulas and para-anastomotic aneurysms are complications of open aortic surgery. Several strategies to deal with these complications are associated with high morbidity and mortality.12,24 Considering increase of life expectancy and the ongoing

discussion on whether or not to treat young and low-risk patients with EVAR, long-term durability is of utmost importance. Long-term follow-up of the infrarenal aortic neck after open aneurysm repair shows a dilatation of 0.5 mm annually.8,9,14 This dilatation may jeopardise long-term results of both open and endovascular abdominal aortic aneurysm repair. To identify patients at risk of developing proximal neck dilatation, several predictive risk factors have been shown. Patients with large aortic aneurysm necks, large abdominal aneurysms or circumferential aortic neck thrombus are prone to develop aortic neck enlargement after EVAR of the infrarenal AAA.25 Traditional teaching of OR dictates creation of the proximal anastomosis immediately distal to the renal arteries; however, this objective can only be achieved using suprarenal clamping.

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Theoretically, this technique uses the best quality wall (pararenal), and it would prevent long-term complications from continued aneurysmal dilatation of the infrarenal aorta. This study proves it is difficult for a surgeon to assess the correct position of the graft; only 6% of the 84 surgeons were correct in their estimation of whether the graft was within 10 mm of the caudal renal artery. Our study consists of a unique set of patients with long infrarenal necks as they were all considered suitable for EVAR. One might argue that current OR patients all lack a suitable neck and that juxtarenal aneurysm repair is more appropriate in these patients. Our study does indicate that the placement of a clamp at an infrarenal neck leaves at least 1 cm of native aorta in situ, prone to further dilatation. Other studies indicate that drug treatment might play an essential role in preventing AAA growth and thus might have the potential to attenuate or slowing down the process of aortic neck dilatation as well.26,27 In the OR group, about one-fourth of the patients at risk 5 years after randomisation had a CT scan; of these 34 patients, two (5.8%) had a para-anastomotic aneurysm. In future study designs comparing EVAR to OR of AAAs, long-term CT scan follow-up is warranted.

CONCLUSION

After open AAA repair, a longer segment of the infrarenal aortic neck is left untreated compared with endovascular AAA repair , and most surgeons underestimate the length of this segment. Whether this underestimation results in more long-term problems at the proximal aortic neck is subject to further study.

60 | CHAPTER 5

REFERENCES

1. Pintoux D, Chaillou P, Azema L, Bizouarn P, Costargent A, Patra P, et al. Longterm influence of suprarenal or infrarenal fixation on proximal neck dilatation and stentgraft migration after EVAR. Ann Vasc Surg 2011;25(8):1012-9.

2. Goodney PP, Tavris D, Lucas FL, Gross T, Fisher ES, Finlayson SR. Causes of late mortality after endovascular and open surgical repair of infrarenal abdominal aortic aneurysms. J Vasc Surg 2010;51(6):1340-7.

3. Crawford ES, Saleh SA, Babb 3rd JW, Glaeser DH, Vaccaro PS, Silvers A. Infrarenal abdominal aortic aneurysm: factors influencing survival after operation performed over a 25-year period. Ann Surg 1981;193(6):699-709.

4. Diehm N, Dick F, Katzen BT, Schmidli J, Kalka C, Baumgarter I. Aortic neck dilatation after endovascular abdominal aortic aneurysm repair: a word of caution. J Vasc Surg 2008;47:886-92.

5. Tonnessen BH, Sternbergh WC, Money SR. Late problems at the proximal aortic neck: migration and dilatation. Semin Vasc Surg 2004;17:288-93.

6. Monahan TS, Chuter TA, Reilly LM, Rapp JH, Hiramoto JS. Long-term follow-up of neck expansion after endovascular aortic aneurysm repair. J Vasc Surg 2010;52(2):303-7.

7. Falkensammer J, Oldenburg WA, Biebl M, Hugl B, Hakaim AG, Crook JE, et al. Abdominal aortic aneurysm neck remodeling after open aneurysm repair. J Vasc Surg 2007;45(5):900-5.

8. Cao P, De Rango P, Parlani G, Verzini F. Fate of proximal aorta following open infrarenal aneurysm repair. Semin Vasc Surg 2009;22(2):93-8 [Review].

9. Lipski DA, Ernst CB. Natural history of the residual infrarenal aorta after infrarenal abdominal aortic aneurysm repair. J Vasc Surg 1998;27:805-11.

10. Liapis C, Kakisis J, Kaperonis E, Papavassiliou V, Karousos D, Tzonou A, et al. Changes of the infrarenal aortic segment after conventional abdominal aortic aneurysm repair. Eur J Vasc Endovasc Surg 2000;19:643-7.

11. Biancari F, Ylonen K, Anttilla V, Juvonen J, Romsi P, Satta J, et al. Durability of open repair of infrarenal abdominal aortic aneurysm: a 16 year follow-up study. J Vasc Surg 2002;35:87-93.

12. Sachdev U, Baril DT, Morrissey NJ, Silverberg D, Jacobs TS, Marin ML, et al. Endovascular repair of para-anastomotic aortic aneurysms. J Vasc Surg 2007;46:636-41.

13. Mulder EJ, van Bockel JH, Maas J, van den Akker PJ, Hermans J. Morbidity and mortality of reconstructive surgery of non infected false aneurysms detected long after aortic prosthetic reconstruction. Arch Surg 1998;133:45-9.

14. Sonesson B, Resch T, Lanne T, Ivanec K. The fate of the infrarenal aortic neck after open aneurysm surgery. J Vasc Surg 1998;28:889-94.

15. Curl GR, Faggioli GL, Stella A, DÁddato M, Ricotta JJ. Aneurysmal change at or above the proximal anastomosis after infrarenal aortic grafting. J Vasc Surg 1992;16:855-9.

16. Allen RC, Schneider J, Longenecker L, Smith 3rd RB, Lumsden AB. Para-anastomotic aneurysms of the abdominal aorta. J Vasc Surg 1993;18:424-31.

17. Prinssen M, Wever JJ, Mali WP, Eikelboom BC, Blankensteijn JD. Concerns for the durability of the proximal abdominal aortic aneurysm endograft fixation from a 2-year and 3-year longitudinal computed tomography angiography study. J Vasc Surg 2001;33(2 Suppl):S64-9.

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18. Wever JJ, de Nie AJ, Blankensteijn JD, Broeders IA, Mali WP, Eikelboom BC. Dilatation of the proximal neck of infrarenal aortic aneurysms after endovascular AAA repair. Eur J Vasc Endovasc Surg 2000;19(2):197-201.

19. Rodway AD, Powell JT, Brown LC, Greenhalgh RM. Do abdominal aortic aneurysm necks increase in size faster after endovascular than open repair? Eur J Vasc Endovasc Surg 2008;35(6):685-93.

20. Dalainas I, Xiromeritis K. Aortic neck dilatation and endograft migration after EVAR. J Endovasc Ther 2010;17(6):685-6.

21. van Prehn J, Schlösser FJ, Muhs BE, Verhagen HJ, Moll FL, van Herwaarden JA. Oversizing of aortic stent grafts for abdominal aneurysm repair: a systematic review of the benefits and risks. Eur J Vasc Endovasc Surg 2009;38(1):42-53. Epub 2009 May 9 [Review].

22. Prinssen M, Buskens E, Blankensteijn JD. The Dutch Randomised Endovascular Aneurysm Management (DREAM) trial. Backround, design and methods. J Cardiovasc Surg (Torino) 2002;43:379-84.

23. Wever JJ, Blankensteijn JD, van Rijn JC, Broeders IA, Eikelboom BC, Mali WP. Inter- and intra-observer variability of CT measurements obtained after endovascular repair of abdominal aortic aneurysms. AJR Am J Roentgenol 2000;175(5):1279-82.

24. El Sakka K, Halawa M, Kotze C, Francis I, Doyle T, Yusuf W. Complications of open abdominal aortic surgery: the endovascular solution. Interact Card Vasc Thor Surg 2008;7:121-5.

25. Cao P, Verzini F, Parlani G, De Rango P, Parente B, Maselli A. Predictive factors and clinical consequences of proximal aortic neck dilatation in 230 patients undergoing abdominal aorta aneurysm repair with self-expandable stent grafts. J Vasc Surg 2003;37:1200-5.

26. Diehm N, Baumgartner I. ACE inhibitors and abdominal aortic aneurysm. Lancet 2006;368: 622-3.

27. Hackam DG, Thiruchelvam D, Redelmeijer DA. Angiotensin-converting enzyme inhibitors and aortic rupture: a population based case-control study. Lancet 2006;368:695-765.

Renal function five years after open and endovascular aortic aneurysm repair from a randomized trial

Chapter 6

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BACKGROUND

Since the introduction of endovascular aortic aneurysm repair (EVAR), subsequent renal dysfunction has been a concern. Chronic renal failure is a major public health problem associated with high costs and poor outcomes1–4. Renal dysfunction, defined as a decline in estimated glomerular filtration rate (eGFR), is a strong predictor of impaired survival, especially after vascular surgery5–8. During EVAR, renal dysfunction is of specific concern owing to the administration of nephrotoxic contrast agents and instrumentation in the juxtarenal aorta. Contrast induced nephropathy is an important complication of radiographic contrast administration. It is the third leading cause of hospital-acquired renal insufficiency, and so every vascular interventionist should be aware of the strategies to prevent this9. However, several prospective studies with short- and mid-term results have failed to substantiate the enhanced risk of renal dysfunction after the early postoperative phase10–12. In comparison with open aneurysm repair (OR), the less invasive nature of EVAR and the absence of infrarenal aortic cross-clamping reduces the risk of renal dysfunction directly after surgery13,14. During follow-up, however, EVAR has higher reintervention rates than OR15,16 and, together with the use of contrast-enhanced computed tomography (CT) follow-up, the presumed initial advantages of EVAR for kidney function may be negated or even outweighed. Preoperative kidney function should not drive the decision between OR and EVAR, yet there is evidence that chronic renal impairment is a good predictor of both worse short- and long-term outcomes after abdominal aortic aneurysm (AAA) surgery5–8. The aim of this study was to compare renal function five years after OR and EVAR for AAA.

METHODS

This was a post hoc analysis of data from the Dutch Randomized Endovascular Aneurysm Management (DREAM) trial. The design and methods of the trial have been described in detail17. In brief, patients referred to vascular surgery departments at 26 centres in the Netherlands and four in Belgium, with an AAA of at least five cm in diameter and considered suitable candidates for both techniques, were assigned randomly to OR or EVAR. For the present analysis, data acquisition stopped on 1 February 2009. At this time, all living patients had completed follow-up for at least five years. During the first two years of the trial all of these patients had follow-up CT, so the number of scans over this time was quite similar. CT was carried out after discharge, six months, one year, 18 months and two years. In the three years thereafter it was at the discretion of the surgeon whether to acquire additional CT scans. Serum creatinine levels were measured before surgery (baseline), on the first or second day after surgery, and five

66 | CHAPTER 6

years thereafter. The eGFR was determined using the four-point Modification of Diet in Renal Disease (MDRD) formula18 to compare the results with previous publications, and the more precise Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation19. The severity of renal disease was staged using the chronic kidney disease (CKD) classification of the US National Kidney Foundation clinical guidelines, which comprises five classes20: stages 1–5 with an eGFR of at least 90, 60–89, 30–59, 15–29 and less than 15 ml per min per 1.73m2 respectively. Continuous data is presented as mean (SD) if normally distributed, and median (interquartile range) otherwise, with statistical analysis using Student’s t test and Mann–Whitney U test respectively. The χ2 test was used for analysis of proportions and a paired t-test for comparison of mean values for all patients over time. Mean differences are shown with 95% confidence intervals (CI). P <0.050 was considered statistically significant. All analyses were performed using SPSS® version 19.0 software (IBM, Armonk, New York, USA).

RESULTS

Of the 351 patients randomized initially, 335 were discharged alive after AAA repair. 162 patients had died or had unknown creatinine levels for other reasons at five years. The remaining 189 patients had known creatinine levels five years after surgery and form the population for this analysis (Table 1). The eGFR values of these 189 patients at five years were compared with preoperative values. Some 163 (94.2 per cent) of 173 patients who had OR and 132 (81.5 per cent) of 162 who had EVAR had available two-day postoperative creatinine levels. Creatinine levels were available only on the first day after surgery for ten (5.8 per cent) and 30 (18.5 per cent) patients respectively. Of the 189 patients whose renal function could be followed for five years, 94 had undergone OR and 95 EVAR.There were no differences in baseline characteristics including age, sex, Society for Vascular Surgery/International Society for Cardiovascular Surgery risk factor score, aneurysm size or preoperative eGFR between the two treatment groups (Table 2). The eGFR (MDRD formula) declined over time, with a mean preoperative value of 70.9 (16.0) ml per min per 1.73m2 compared with 67.0 (20.7) ml per min per 1.73m2 after five years (mean difference 3.9 (95% CI 1.3 to 6.5) ml per min per 1.73m2; P = 0.003) (Fig. 1A). According to the CKD-EPI equation, the eGFR declined from 80.0 (7.6) to 75.7 (9.7) ml per min per 1.73m2 after five years (mean difference 4.2 (95% CI 3.2 to 5.3) ml per min per 1.73m2; P <0.001) (Fig. 1B). Five years after surgery, the mean eGFR (MDRD formula) was 67.6 (20.4) ml per min per 1.73m2 following OR and 66.0 (21.1) ml per min per 1.73m2 after EVAR (mean difference 1.7 (95% CI −4.3 to 7.6) ml per min per 1.73m2; P = 0.583) (Fig. 1A). Similarly, eGFR calculated by the CKD-EPI equation showed no significant

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difference after five years: 76.3 (9.3) and 75.1 (10.0) ml per min per 1.73m2 after OR and EVAR respectively (mean difference 1.2 (95% CI −1.6 to 3.9) ml per min per 1.73m2; P = 0.410) (Fig. 1B).

Table 1 Baseline characteristics of all patients in the DREAM trial

Alive and known creatinine level (n = 189)

Dead or unknown creatinine level (n = 162)

P†

Age (years)* 69.0(6.8) 71.5(6.3) < 0.001‡

Sex ratio (M : F) 172 : 17 150 : 12 0.698

Mild, moderate, severe SVS/ISCVS factors

Diabetes mellitus 19 (10.1) 16 (9.9) 1.000

Tobacco use 99 (52.4) 108 (66.7) 0.009

Hypertension 112 (59.3) 86 (53.1) 0.146

Dyslipidaemia 98 (51.9) 73 (45.1) 0.239

Carotid artery disease 19 (10.1) 33 (20.4) 0.010

Cardiac disease 81 (42.9) 74 (45.7) 0.666

Renal disease 14 (7.4) 15 (9.3) 0.331

Pulmonary disease 37 (19.6) 44 (27.2) 0.100

Maximum aneurysm diameter (mm)

Mean(s.d.) 59.7(8.5) 61.1(9.0) 0.142‡

Median 58.0 (IQR 54.0-64.0) 58.0 (IQR 55.0-66.0) 0.120§

Preop. eGFR (ml per min per 1.73 m2)*

MDRD formula 70.9(16.0) 72.4(18.0) 0.418‡

CKD-EPI equation 80.0(7.6) 79.2(8.4) 0.390‡

Chronic kidney disease classification

MDRD formula 0.563

Stage 1 22 (11.6) 24 (14.8)

Stage 2 124 (65.6) 100 (61.7)

Stage 3 43 (22.8) 37 (22.8)

Stage 4 0 (0) 1 (0.6)

CKD-EPI equation 0.353

Stage 1 12 (6.3) 14 (8.6)

Stage 2 176 (93.1) 145 (89.5)

Stage 3 1 (0.5) 3 (1.9)

Values in parentheses are percentages unless indicated otherwise: *values are mean(s.d.). SVS/ISCVS, Society for Vascular Surgery/International Society for Cardiovascular Surgery; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration. †c2 test, except ‡Student’s t test and §Mann–Whitney U test.

68 | CHAPTER 6

Table 2 Baseline characteristics of patients who had open or endovascular repair, with glomerular filtration rate available at 5 years

Open repair (n = 94)

Endovascular repair(n = 95) P†

Age (years)* 68.6(7.5) 69.4(6.2) 0.471‡

Sex ratio (M : F) 85 : 9 87 : 8 0.805

Mild, moderate, severe SVS/ISCVS factors

Diabetes mellitus 10 (11) 9 (9) 0.814

Tobacco use 43 (46) 56 (59) 0.081

Hypertension 53 (56) 59 (62) 0.461

Dyslipidaemia 54 (57) 44 (46) 0.146

Carotid artery disease 6 (6) 13 (14) 0.145

Cardiac disease 46 (49) 35 (37) 0.107

Renal disease 7 (7) 7 (7) 1.000

Pulmonary disease 14 (15) 23 (24) 0.142

Maximum aneurysm diameter (mm)

Mean(s.d.) 59.9(8.8) 59.6(8.2) 0.970‡

Median 58.0 (IQR 54.0-60.0) 57.0 (IQR 54.0-63.0) 0.878§

Preop. eGFR (ml per min per 1.73 m2)*

MDRD formula 71.0(15.6) 70.8(16.4) 0.934‡

CKD-EPI equation 80.2(7.7) 79.8(7.5) 0.684‡

Chronic kidney disease classification

MDRD formula 0.848

Stage 1 12 (13) 10 (11)

Stage 2 60 (64) 64 (67)

Stage 3 22 (23) 21 (22)

CKD-EPI equation 0.122

Stage 1 9 (10) 3 (3)

Stage 2 85 (90) 91 (96)

Stage 3 0 (0) 1 (1)

Values in parentheses are percentages unless indicated otherwise: *values are mean(s.d.). SVS/ISCVS, Society for Vascular Surgery/International Society for Cardiovascular Surgery; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; CKD-EPI, Chronic Kidney Disease Epidemiology Collaboration. †c2 test, except ‡Student’s t test and §Mann–Whitney U test.

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A

B

Figure 1 Mean estimated glomerular filtration rate using A Modification of Diet in Renal Disease (MDRD) formula and B Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation before and after open and endovascular aneurysm repair. Error bars represent confidence intervals. * Patients with known creatinine levels and alive after 5 years; †including patients with some data missing

70 | CHAPTER 6

The mean absolute change from preoperative eGFR (MDRD formula) to five-year eGFR was −0.6 (3.3) ml per min per 1.73m2 per year after OR and −0.9 (3.9) ml per min per 1.73m2 per year after EVAR (mean difference 0.3 (95% CI −0.7 to 1.4) ml per min per 1.73m2 per year; P = 0.551). Using CKD-EPI, respective values were −0.8 (1.3) and −0.9 (1.5) ml per min per 1.73m2 per year (mean difference 0.1 (95% CI −0.3 to 0.6) ml per min per 1.73m2 per year; P =0.480). There were no differences between CKD stages and treatment group before operation (Table 2) or after five years. However, in both groups more patients were in CKD stage 3 after five years than before operation. After five years, 31 patients in the OR group and 30 in the EVAR group were at CKD stage 3 (MDRD formula), compared with 22 and 21 patients respectively before their operation. Six patients had progressed to stage 4: two after OR and four following EVAR (P = 0.865). One patient in each group developed chronic renal failure requiring dialysis. Two patients died from dehydration and renal failure, one in the EVAR group after obstructive bowel disease and one in the OR group. The other causes of death have been described elsewhere16. To evaluate the possibility of selection bias in the present study population owing to dropouts, the mean perioperative eGFR of patients alive with known creatinine levels after five years was compared with that of patients whose creatinine levels were not available after five years (Table 1). There were no significant differences, suggesting lack of bias.

DISCUSSION

The eGFR of patients in the DREAM trial declined by a mean of 3.9 (18.0) ml per min per 1.73m2 after five years of follow-up (0.8ml per min per 1.73m2 annually). This decline in eGFR is similar to that recorded in the EVAR 1 trial (range −0.76 to −1.13 ml per min per 1.73m2 per year). Neither study found any difference in renal function, after five and three years respectively, between EVAR and OR. These two independent cohorts together reassure the external validity of this conclusion. Compared with large population-based studies (National Health and Nutrition Examination Survey, NHANES III), patients in the DREAM trial had lower preoperative mean eGFR than their age-matched, healthier counterparts20. However, the subsequent decline in their GFR over time is in accordance with findings in the general population20,21. This suggests that, in terms of kidney function, both OR and EVAR are safe in a population with mainly stage 2 CKD. These results are in line with the EVAR trials, which showed that patients who survive the first year would have stable renal function for at least three years, with no significant difference between EVAR and OR12. Several other prospective trials have confirmed these results10,11. A possible drawback of follow-up limited to five years is that the number of subsequent reinterventions might differ between treatment groups, with different effects on

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renal function. Longer-term follow-up of renal function might clarify this. A subset of patients remain at risk of deteriorating renal function after AAA repair, especially those with more advanced pre-existing renal impairment8,22–24.These patients are more likely to have higher morbidity and mortality rates than those with relatively normal renal function5–8. Long-term survival after elective aneurysm repair has improved over time despite a change in case mix towards older patients with more co-morbidities25. Several strategies have been proposed to preserve renal function after AAA repair, including remote ischaemic preconditioning, use of N-acetylcysteine or methylprednisolone, and targeted renal therapy26–31. Stent-graft improvement, in combination with these strategies, may decrease renal impairment and consequently chronic renal failure. The accuracy of the estimation of GFR is limited, particularly for the MDRD formula in subjects with relatively normal GFR; 30% of estimates are out of range compared with measured GFR19. The MDRD formula and the CKD-EPI equation were both used here, in order to compare these results with published data. However, a large proportion of the eGFR values were above 60ml per min per 1·73m2, so the CKD-EPI equation was more reliable as a predictor of risk than the MDRD formula, especially in patients with normal creatinine levels and eGFR32,33. The present study has several limitations. First, creatinine levels were not available at five years after surgery for all living patients. However, there was no significant difference between mean eGFR at baseline or after surgery between groups. Another limitation is the lack of information on change in body composition over time, as weight loss will underestimate the eGFR using both methods. In a randomized trial it is likely that changes will be similar after both procedures. After two years the number of CT investigations was not collected. It is likely that the amount of contrast used in the EVAR group was higher than after OR. Finally, no conclusions about the effects of OR and EVAR on renal function can be drawn for patients with more advanced kidney disease. These patients are more likely to experience further renal dysfunction after aortic surgery, with higher morbidity and mortality rates8.

CONCLUSION

Renal function five years after OR and EVAR for AAA was similar. Neither surgical procedure accelerated the loss of renal function.

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16. De Bruin JL, Baas AF, Buth J, Prinssen M, Verhoeven EL, Cuypers PWet al.; DREAM Study Group. Long-term outcome of open or endovascular repair of abdominal aortic aneurysm. N Engl J Med 2010; 362: 1881–1889.

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29. Turner S, Derham C, Orsi NM, Bosomworth M, Bellamy MC, Howell SJ. Randomized clinical trial of the effects of methylprednisolone on renal function after major vascular surgery. Br J Surg 2008; 95: 50–56.

30. Walsh SR, Boyle JR, Tang TY, Sadat U, Cooper DG, Lapsley M et al. Remote ischemic preconditioning for renal and cardiac protection during endovascular aneurysm repair: a randomized controlled trial. J Endovasc Ther 2009; 16: 680–689.

31. Walsh SR, Sadat U, Boyle JR, Tang TY, Lapsley M, Norden AG et al. Remote ischemic preconditioning for renal protection during elective open infrarenal abdominal aortic aneurysm repair: randomized controlled trial. Vasc Endovascular Surg 2010; 44: 334–340.

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32. Matsushita K, Mahmoodi BK,Woodward M, Emberson JR, Jafar TH, Jee SH et al.; Chronic Kidney Disease Prognosis Consortium. Comparison of risk prediction using the CKDEPI equation and the MDRD study equation for estimated glomerular filtration rate. JAMA 2012; 307: 1941–1951.

33. O’Callaghan CA, Shine B, Lasserson DS. Chronic kidney disease: a large-scale population-based study of the effects of introducing the CKD-EPI formula for eGFR reporting. BMJ Open 2011; 1: e000308.

Quality of life after open and endovascular repair of abdominal aortic aneurysms

Chapter 7

7

QUALITY OF LIFE | 77

BACKGROUND

Endovascular aneurysm repair (EVAR) offers a short-term survival and morbidity benefit in patients with an abdominal aortic aneurysm (AAA)1–3. However, long-term survival rates after open and endovascular repair are similar, with more secondary interventions occurring after EVAR3–5. Consequently, other markers of treatment effect such as health-related quality of life (HRQoL) and health status (HS) have gained interest. A recent systematic review6 of quality of life (QoL) was unable to draw any robust conclusions regarding the relative benefit of different treatment strategies, and highlighted the lack of data concerning the impact of postoperative symptoms on QoL. With respect to individual studies, the results are variable. EVAR was associated with a QoL advantage in the immediate postoperative period in several studies7–10, whereas others11–14 showed no significant difference between treatment strategies. Reported short-term benefits after EVAR in some studies8,14 were not sustained after three months, and were offset by worse mid-term QoL scores. Furthermore, this mid-term difference in QoL in favour of open repair could not be reproduced by other groups7,12. Long-term results of only a single randomized trial15 are known, with no explicit benefit of either treatment modality regarding QoL. Two recent systematic reviews16,17 suggested a significant deterioration in QoL following aneurysm repair, which may be more pronounced following open repair compared with EVAR at three and 12 months. The aim of this study was to evaluate long-term HRQoL and health status after EVAR and open AAA surgery.

METHODS

The design and methods of the DREAM (Dutch Randomized Endovascular Aneurysm Repair) trial have been described in detail elsewhere18. In brief, patients referred to surgery clinics at 26 centres in the Netherlands and four centres in Belgium, who had received a diagnosis of AAA of at least five cm in diameter and were considered suitable candidates for both techniques, were assigned randomly to undergo open or endovascular repair after giving written informed consent. The study was performed according to the principles of the Declaration of Helsinki. The institutional review boards of all participating hospitals approved the protocol and the follow-up extension. The primary informed consent covered two years of follow-up for all patients. A secondary written informed consent for an additional three years of follow-up was requested from all patients who had completed the initial two years. All data were submitted to the trial coordination centre (Julius Centre for Health Sciences and Primary Care, University Medical Centre, Utrecht, The Netherlands). For the present analysis, data acquisition was stopped on 1 February 2009 and included five years of follow-up for every patient. The

78 | CHAPTER 7

long-term primary endpoint of the DREAM trial was the rate of death from any cause and reintervention, and as published previously5. Prespecified secondary endpoints included health status and HRQoL as assessed using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36®; QualityMetric, Lincoln, Rhode Island, USA) and the EuroQol 5D (EQ-5D™) instrument (EuroQol, Rotterdam, The Netherlands)19–21. Despite considerable overlap, information on both scores was obtained to allow comparison with existing studies7–14, and because neither has been validated in studying this disease process. The SF-36® evaluates eight dimensions of HRQoL: physical function, social function, role physical, role emotional, mental health, vitality, bodily pain and general health. All the SF-36® scores are norm-based using QualityMetric software, including calculation of the physical component summary (PCS) and mental component summary (MCS) scores22,23. Using norm-based scores, setting scores at a mean of 50 for each domain makes it easier to interpret the trial data and allows comparison with other diseases or groups of patients using the same measuring tools23,24. The EQ-5D™ assesses five items, defining health in terms of: mobility, self-care, usual activities, pain/discomfort and anxiety/depression21. It includes a descriptive score and a visual analogue scale (VAS) score. The EQ-5D™ descriptive utility scores are on a scale from 0 to 1, and all other scores on a scale from 0 to 100. Higher scores indicate better health status and HRQoL for both instruments. Patients were requested to complete questionnaires at baseline (before surgery) and after aneurysm repair at 3 weeks, 6 weeks, 3 months, 6 months, and then every 6 months until 5 years. Where questionnaires were not returned, patients received a reminder telephone call and letter. Questionnaires that were returned incomplete were completed by telephone call if possible. All data was analysed according to the intention-to-treat principle. For descriptive statistics (baseline characteristics) continuous data is presented as mean (SD) when distributed normally and median (IQR) for data with a non-normal distribution; differences between treatment groups were evaluated with the Student’s t-test or Mann–Whitney U test respectively. The χ2 test was used for comparison of proportions. These analyses were performed using SPSS® version 19.0 software (IBM, Armonk, New York, USA). Previous studies 8,14 suggested that there is a difference in the effect of open repair compared EVAR between the intervals shortly after the intervention compared with mid/long-term follow-up. A distinction was made between short-term effects (effects 0 and 6 weeks after intervention) and longer-term effects (effects observed between 3 and 60 months after intervention). Patients who failed to complete HRQoL questionnaires at baseline were excluded from the present analyses. For each patient, HRQoL outcomes were measured repeatedly over time. To account for the dependency of observations within patients, a conventional linear mixed-effects model was used with an autoregressive correlation structure (correlation structure of the errors was an autoregressive correlation structure), adjusting for the baseline value of the HRQoL outcome, which best fitted the repeated measurements in

7


the data25. Data was analysed assessing the difference in mean QoL (and its subscales) between the two intervention arms at each of the follow-up times. Importantly, as stated above, this model takes dependencies of measurements within individuals into account (and is thus different from analysing all time points separately). Usually, such a linear mixed-effects model includes an interaction between time and intervention, allowing for different treatment effects at the different time points. Because treatment effects did not differ during long-term follow-up, indicated by a non-significant interaction in the analyses, the interaction was omitted from the model and consequently a single treatment effect could be presented. This treatment effect should be interpreted as the mean difference in QoL between the two intervention arms at each of the long-term time points. To assess the impact of mortality or reinterventions on the effect HRQoL after open versus endovascular repair, additional analyses were performed, in which both mortality and reintervention status were includedas a co-variable in the model from the time of intervention onwards. All these analyses were performed using R (R Foundation for Statistical Computing, Vienna, Austria).

RESULTS

From November 2000 to December 2003 178 patients were assigned randomly to undergo open repair and 173 to EVAR. Baseline characteristics are summarized in Table 1. Of these 351 patients, a total of 332 returned QoL questionnaires during the trial period in both groups. More than 70% of questionnaires were returned at each time point (Figure 1). QoL and health status, as assessed by SF-36® and EQ-5D™ descriptive and VAS scores, were similar between the EVAR and open repair Both surgical interventions had a negative impact on HRQoL and health status (Table 2, Figures 2 and 3). This was less severe in the EVAR group than in the open repair group, especially in the physical domains of SF-36® (Table 3). Six weeks after surgery, physical function was better following EVAR than open repair: mean score difference 3.61 (95% CI 1.64 to 5.58). Role physical results also favoured EVAR: mean score difference 3.83 (95% CI 1.82 to 5.83). These improved scores after EVAR resulted in a higher PCS score in this group: mean difference 2.60 (95% CI 1.00 to 4.20).

80 | CHAPTER 7

Table 1 Baseline characteristics

Open repair Endovascular repair

(n = 178) (n =173)

Age (years)* 69.6(6.8) 70.7(6.6)

Sex (M : F) 161 : 17 161 : 12

Aneurysm size (mm)* 60.1(8.5) 60.6(9.0)

SVS/ISCVS risk factors Diabetes mellitus

No 161 (90.4) 155 (89.6)

Mild 14 (7.9) 16 (9.2)

Moderate 3 (1.7) 2 (1.2)

Severe 0 (0) 0 (0)

Tobacco use

No 81 (45.5) 63 (36.4)

Mild 37 (20.8) 41 (23.7)

Moderate 45 (25.3) 61 (35.3)

Severe 15 (8.4) 8 (4.6)

Hypertension

No 81 (45.5) 72 (41.6)

Mild 53 (29.8) 65 (37.6)

Moderate 37 (20.8) 33 (19.1)

Severe 7 (3.9) 3 (1.7)

Carotid disease

No 151 (84.8) 148 (85.5)

Mild 8 (4.5) 4 (2.3)

Moderate 13 (7.3) 16 (9.2)

Severe 6 (3.4) 5 (2.9)

Cardiac disease

No 94 (52.8) 102 (59.0)

Mild 70 (39.3) 59 (34.1)

Moderate 14 (7.9) 12 (6.9)

Severe 0 (0) 0 (0)

Renal disease

No 162 (91.0) 160 (92.5)

Mild 15 (8.4) 13 (7.5)

Moderate 1 (0.6) 0 (0)

Severe 0 (0) 0 (0)

Pulmonary disease

No 145 (81.5) 125 (72.3)

Mild 22 (12.4) 38 (22.0)

Moderate 10 (5.6) 10 (5.8)

Severe 1 (0.6) 0 (0)

Values in parentheses are percentages unless indicated otherwise; *values are mean(s.d.). SVS/ISCVS, Society for Vascular Surgery/International Society for Cardiovascular Surgery.

7


Figure 1 Percentage of questionnaires returned at each time point

Figure 2A Physical component summary scores after open and endovascular abdominal aortic aneurysm repair. Values are mean with 95 per cent confidence intervals

82 | CHAPTER 7

Figure 2B Mental component summary scores after open and endovascular abdominal aortic aneurysm repair. Values are mean with 95 per cent confidence intervals.

Figure 3A EuroQol-5D (EQ-5™) descriptive scores after open and endovascular abdominal aortic aneurysm repair. Values are mean with 95 per cent confidence intervals.

7


Figure 3B EuroQol-5D (EQ-5™) visual analogue scale (VAS) scores after open and endovascular abdominal aortic aneurysm repair. Values are mean with 95 per cent confidence intervals.

Table 2 Overall changes in quality of life 0–3 weeks after intervention, irrespective of randomization group

Score difference P

Mental component summary –2.84 (–4.27, –1.41) < 0.005

Physical component summary –9.31 (–10.49, –8.14) < 0.005

SF-36®

Physical functioning –9.00 (–10.28, –7.71) < 0.005

Role functioning –10.73 (–12.42, –9.03) < 0.005

Bodily pain –8.48 (–10.14, –6.83) < 0.005

General –0.79 (–1.72, 0.15) 0.100

Vitality –6.04 (–7.28, –4.81) < 0.005

Social functioning –11.17 (–12.75, –9.59) < 0.005

Role emotional –6.04 (–8.05, –4.03) < 0.005

Mental health –0.24 (–1.58, 1.11) 0.730

EQ-5D™ VAS –5.94 (–8.02, –3.85) < 0.005

EQ-5D™ descriptive –0.13 (–0.17, –0.09) < 0.005

Values indicate differences in quality-of-life (QoL) score between postoperative and baseline values for the whole study population, with 95 per cent confidence intervals in parentheses. Positive values indicate QoL improvement compared with preoperative baseline values, whereas negative values show deterioration. SF, Short Form; EQ, EuroQol; VAS, visual analogue scale. *Linear mixed-effects model with an autoregressive correlation structure.

84 | CHAPTER 7

Table 3 Effect of surgical intervention on quality of life: difference between endovascular versus open repair

0–6 weeks after

intervention

3–60 months after intervention

3–60 months after intervention (adjusted for

reintervention)

3–60 months after intervention(adjusted for

mortality)Mental component summary 0.81

(–1.41, 3.03)–1.37

(–3.10, 0.36)–1.32

(–3.06, 0.41)–2.96

(–6.40, 0.49)Physical component summary 2.60

(1.00, 4.20)*–1.98

(–3.56, –0.41)*–1.84

(–3.39, –0.30)*–2.69

(–5.75, 0.37)SF-36®

Physical functioning 3.61 (1.64, 5.58)*

–2.56 (–4.17, –0.95)*

–2.42 (–3.99, –0.84)*

–3.25 (–6.12, –0.37)*

Role functioning 3.83 (1.82, 5.83)*

–1.89 (–3.95, 0.16)

–1.75 (–3.77, 0.27)

–2.92 (–6.22, 0.38)

Bodily pain 0.90 (–1.27, 3.06)

–1.32 (–2.97, 0.33)

–1.18 (–2.80, 0.44)

–2.51 (–6.05, 1.04)

General –1.15 (–2.62, 0.31)

–2.14 (–3.52, –0.77)*

–2.09 (–3.46, –0.71)*

–3.52 (–6.51, –0.53)*

Vitality 2.59 (0.73, 4.46)*

–1.17 (–2.53, 0.18)

–1.09 (–2.45, 0.26)

–2.92 (–6.26, 0.42)

Social functioning 3.12 (0.86, 5.39)*

–2.20 (–3.91, –0.49)*

–2.10 (–3.81, –0.39)*

–3.34 (–6.60, –0.08)*

Role emotional 1.71 (–1.11, 4.53)

–1.64 (–3.74, 0.46)

–1.53 (–3.63, 0.56)

–3.02 (–6.50, 0.46)

Mental health –0.45 (–2.50, 1.61)

–1.85 (–3.48, –0.23)*

–1.82 (–3.44, –0.20)*

–3.52 (–6.87, –0.16)*

EQ-5D™ VAS 2.81 (–0.43, 6.05)

–4.09 (–6.91, –1.27)*

–3.92 (–6.74, –1.09)*

–5.35 (–10.44, –0.26)*

EQ-5D™ descriptive 0.04 (–0.02, 0.09)

–0.06 (–0.10, –0.02)*

–0.06 (–0.10, –0.02)*

–0.07 (–0.13, –0.02)*

Values in parentheses are 95 per cent confidence intervals. Positive values favour endovascular repair over conventional repair, whereas negative values favour open repair. All analyses were adjusted for the baseline measurement. SF, Short Form; EQ, EuroQol; VAS, visual analogue scale. *P < 0.050 (linear mixed-effects model with an autoregressive correlation structure).

Vitality and social function also scored better after EVAR for 6 weeks after surgery: mean difference 2.59 (95% CI 0.73 to 4.46) and 3.12 (0.86 to 5.39) respectively. The EQ-5D™ descriptive utility scores were not statistically different nor were the VAS scores of EQ-5D™. Effects and mean differences for all the domains are listed in Table 3. The short-term effect was more pronounced in the first three weeks after surgery compared with the first six weeks (data not shown). Beyond six weeks, a different pattern was found: scores for physical function and general health were better after open repair than for EVAR: mean difference −2.56 (95% CI –4.17 to −0.95) and −2.14 (−3.52 to −0.77) respectively. These improved scores after open repair resulted in a higher PCS score in this group: mean difference −1.98 (95% CI −3.56 to −0.41). More than six weeks after surgery, mental

7


health and social function scores were better after open repair: mean difference −1.85 (95% CI −3.48 to −0.23) and −2.20 (95% CI −3.91 to −0.49) respectively (Table 3). MCS scores were not significantly different between open and EVAR groups at these time points. Mean PCS and MCS scores over time are shown in Figure 2A and 2B respectively. The EQ-5D™ descriptive and VAS scores were significantly different in favour of open repair at three months: mean difference −0.06 (95% CI −0.10 to −0.02) and −4.09 (95% CI −6.91 to −1.27) respectively. Changes in EQ-5D™ descriptive and VAS scores over time are shown in Figure 3A and 3B respectively. The overall long-term outcomes beyond six weeks were not influenced by adjustment for the 78 reinterventions and mortality that occurred during follow-up (Table 3).

DISCUSSION

A deterioration in QoL occurred early after surgical intervention, especially in the physical domains of SF-36®. Thereafter, in the following months, there was a slower rate of increase in QoL, which reached a plateau that was maintained into longer-term follow-up. A significant difference in several of the predominantly physical domains of SF-36® was observed between groups at these time intervals, at first in favour of EVAR and subsequently favourable for open repair (Table 3). This data builds on published mid-term data by providing HRQoL information on twice the number of patients at two years and accounting for the burden of reintervention to five years after aneurysm repair. A significant drop in QoL was reported immediately after AAA repair in several previous studies7–10. In contrast, other studies11–13 found no significant differences in QoL between the treatments. Two randomized clinical trials 7,8, including the authors’ initial results, showed a significant benefit in terms of health status or HRQoL, particularly in the physical domains immediately after EVAR. However, these short-term differences in the DREAM8 and EVAR-17 trials could not be reproduced in the OVER (Open Versus Endovascular Repair) trial12; the reported HRQoL scores at one and two years after surgery were similar after EVAR and open surgery. In the present study, a significant long-term difference was observed between open and EVAR, which appeared to favour open repair, in several domains of SF-36® and in EQ-5D™. This long-term difference was not reported in the OVER trial 15 or a recent meta-analysis 16 on the subject, although follow-up in the latter was restricted to 12 months. Conflicting results for pooled data reported in the meta-analysis 16 may relate to the short length of follow-up, with fewer reinterventions and cardiovascular events to influence HRQoL.There are several limitations or uncertainties associated with this study. Firstly, although the SF-36® and EQ-5D™ generic questionnaires are used widely and have been validated, they are not specific to patients undergoing AAA surgery. Furthermore, the subjectiveness

86 | CHAPTER 7

of patient-reported outcomes is inescapable. Patients who undergo large laparotomies, such as those during open AAA repair, expect to have postoperative discomfort, whereas patients who have minimally invasive surgery, such as EVAR, expect to recover rapidly and have few ongoing problems in the longer term. As such, any deviation from such expectations influences self-reported QoL scores in the perioperative period and potentially in the longer term. Patient understanding of the need for lifelong surveillance following EVAR may, however, influence long-term outcomes and possibly account for some of the sustained differences in the measures reported here. The intensified follow-up protocol two years and beyond EVAR could explain the mid/long-term differences. These patients are reminded of their aneurysm repair each time they enter the hospital. This influence may be greater in the EVAR arm as the burden of surveillance in long-term follow-up is considerable. Although patients in the EVAR group underwent annual CT surveillance from the second postoperative year onwards, those in the open group were not actively in a surveillance programme beyond two years. Nevertheless, the follow-up protocols during the first two years of this trial were the same for both treatment arms and differences already existed at three months after surgery. There could have been a co-variable shift over time owing to mortality benefit between the different treatment modalities; if a greater number of patients had died in either the EVAR or conventional aneurysm repair group, QoL in the remaining patients might have appeared better. This explanation is unlikely because the present randomized clinical trial showed no long-term difference in survival. Finally, reinterventions after both treatment strategies did not account for the difference between groups in HRQoL or health status; differences between open and endovascular repair remained after adjustment for this factor in the linear mixed model. The perioperative benefit of EVAR in terms of primary and secondary outcome parameters such as mortality, complications and hospital stay including QoL cannot be ignored. EVAR has significantly reduced short-term morbidity and mortality after AAA repair1–3,26. It is proven that long-term survival after EVAR is equivalent to that after open repair and therefore a safe treatment strategy despite more secondary interventions3,4,15,27. Patient-reported outcomes are becoming increasingly important in clinical medicine, especially in view of the decreasing morbidity and mortality rates. Mortality and morbidity rates should therefore, not be the sole criterion for assessing treatment success28,29. Patient-reported outcomes could have an impact on choice of the appropriate intervention, especially if mortality rates for these two treatment strategies are the same28. Accordingly, this information should be shared with patients and the feasibility of doing so has been demonstrated30. The development of validated tools to measure disease-specific outcomes after aortic aneurysm surgery may go some way to improving understanding of the impact of such interventions on this group of elderly patients.

7


REFERENCES

1. Prinssen M, Verhoeven EL, Buth J, Cuypers PW, van Sambeek MR, Balm R et al.; Dutch Randomized Endovascular Aneurysm Management (DREAM) Trial Group. A randomized trial comparing conventional and endovascular repair of abdominal aortic aneurysms. N Engl J Med 2004; 351: 1607–1618.

2. Greenhalgh RM, Brown LC, Kwong GP, Powell JT, Thompson SG; EVAR trial participants. Comparison of endovascular aneurysm repair with open repair in patients with abdominal aortic aneurysm (EVAR trial 1), 30-day operative mortality results: randomised controlled trial. Lancet 2004; 364: 843–848.

3. United Kingdom EVAR Trial Investigators, Greenhalgh RM, Brown LC, Powell JT, Thompson SG, Epstein D et al. Endovascular versus open repair of abdominal aortic aneurysm. N Engl J Med 2010; 362: 1863–1871.

4. De Bruin JL, Baas AF, Buth J, Prinssen M, Verhoeven EL, Cuypers PWet al. Long-term outcome of open or endovascular repair of abdominal aortic aneurysm. N Engl J Med 2010; 362: 1881–1889.

5. Washington AE, Lipstein SH. The Patient-Centered Outcomes Research Institute – promoting better information, decisions, and health. N Engl J Med 2011; 365: e31.

6. Peach G, Holt P, Loftus I, Thompson MM, Hinchliffe R. Questions remain about quality of life after abdominal aortic aneurysm repair. J Vasc Surg 2012; 56: 520–527.

7. EVAR trial participants. Endovascular aneurysm repair versus open repair in patients with abdominal aortic aneurysm (EVAR trial 1): randomised controlled trial. Lancet 2005; 365: 2179–2186.

8. Prinssen M, Buskens E, Blankensteijn JD; DREAM trial participants. Quality of life endovascular and open AAA repair. Results of a randomised trial. Eur J Vasc Endovasc Surg 2004; 27: 121–127.

9. Lottman PE, Laheij RJ, Cuypers PW, Bender M, Buth J. Health-related quality of life outcomes following elective open or endovascular AAA repair: a randomized controlled trial. J Endovasc Ther 2004; 11: 323–329.

10. Aquino RV, Jones MA, Zullo TG, Missig-Carroll N, Makaroun MS. Quality of life assessment in patients undergoing endovascular or conventional AAA repair. J Endovasc Ther 2001; 8: 521–528.

11. Malina M, Nilsson M, Brunkwall J, Ivancev K, Resch T, Lindblad B. Quality of life before and after endovascular and open repair of asymptomatic AAAs: a prospective study. J Endovasc Ther 2000; 7: 372–379.

12. Lederle FA, Freischlag JA, Kyriakides TC, Padberg FT Jr, Matsumura JS, Kohler TR et al.; Open Versus Endovascular Repair (OVER) Veterans Affairs Cooperative Study Group. Outcomes following endovascular vs open repair of abdominal aortic aneurysm: a randomized trial. JAMA 2009; 302: 1535–1542.

13. Soulez G, Thérasse E, Monfared AA, Blair JF, Choiniére M, Elkouri S et al. Pain and quality of life assessment after endovascular versus open repair of abdominal aortic aneurysms in patients at low risk. J Vasc Interv Radiol 2005; 16: 1093–1100.

14. Aljabri B, AlWahaibi K, Abner D, Mackenzie KS, Corriveau MM, Obrand DI et al. Patient-reported quality of life after abdominal aortic aneurysm surgery: a prospective comparison of endovascular and open repair. J Vasc Surg 2006; 44: 1182–1187.

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15. Lederle FA, Freischlag JA, Kyriakides TC, Matsumura JS, Padberg FT Jr, Kohler TR et al.; OVER Veterans Affairs Cooperative Study Group. Long-term comparison of endovascular and open repair of abdominal aortic aneurysm. N Engl J Med 2012; 367: 1988–1997.

16. Coughlin PA, Jackson D,White AD, Bailey MA, Farrow C, Scott DJ et al. Meta-analysis of prospective trials determining the short- and mid-term effect of elective open and endovascular repair of abdominal aortic aneurysms quality of life. Br J Surg 2013; 100: 448–455.

17. Kayssi A, DeBord Smith A, Roche-Nagle G, Nguyen L. Health-related quality of life outcomes after open versus endovascular abdominal aortic aneurysm repair. J Vasc Surg 2015; 62: 491–498.

18. Prinssen M, Buskens E, Blankensteijn JD. The Dutch Randomised Endovascular Aneurysm Management (DREAM) trial. Background, design and methods. J Cardiovasc Surg (Torino) 2002; 43: 379–384.

19. Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med Care 1992; 30: 473–483.

20. Aaronson NK, Muller M, Cohen PD, Essink-Bot ML, Fekkes M, Sanderman R et al. Translation, validation, and norming of the Dutch language version of the SF-36 Health Survey in community and chronic disease populations. J Clin Epidemiol 1998; 51: 1055–1068.

21. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 2001; 33: 337–343.

22. Ware JE Jr, Kosinski M, Bayliss MS, McHorney CA, Rogers WH, Raczek A. Comparison of methods for the scoring and statistical analysis of SF-36 health profile and summary measures: summary of results from the Medical Outcomes Study. Med Care 1995; 33(Suppl): AS264–AS279.

23. Ware JE Jr, Gandek B. Methods for testing data quality, scaling assumptions, and reliability: the IQOLA Project Approach. International Quality of Life Assessment. J Clin Epidemiol 1998; 51: 945–952.

24. Mallinckrodt CH, Lane PW, Schnell D, Peng Y, Mancuso JP. Recommendations for the primary analysis of continuous endpoints in longitudinal clinical trials. Drug Inf J 2008; 42: 303–319.

25. Stather PW, Sidloff D, Dattani N, Choke E, Bown MJ, Sayers RD. Systematic review and meta-analysis of the early and late outcomes of open and endovascular repair of abdominal aortic aneurysm. Br J Surg 2013; 100: 863–872.

26. Paravastu SC, Jayarajasingam R, Cottam R, Palfreyman SJ, Michaels JA, Thomas SM. Endovascular repair of abdominal aortic aneurysm. Cochrane Database Syst Rev 2014; (1)CD004178.

27. Brown LC, Thompson SG, Greenhalgh RM, Powell JT; Endovascular Aneurysm Repair (EVAR) trial participants. Incidence of cardiovascular events and death after open or endovascular repair of abdominal aortic aneurysm in the randomized EVAR trial 1. Br J Surg 2011; 98: 935–942.

28. Scarpa M. Quality of life after surgery of the alimentary tract. World J Gastroenterol 2010; 16: 5020–5023.

29. Brundage M, Feldman-Stewart D, Leis A, Bezjak A, Degner L, Velji K et al. Communicating quality of life information to cancer patients: a study of six presentation formats. J Clin Oncol 2005; 23: 6949–6956.

30. Gandek B,Ware JE Jr. Methods for validating and norming translations of health status questionnaires: the IQOLA Project approach. International Quality of Life Assessment. J Clin Epidemiol 1998; 51: 953–959.

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Summary and general discussion

Chapter 8

8

SUMMARY AND GENERAL DISCUSSION | 93

SUMMARY AND GENERAL DISCUSSION

One of the main findings of this study was that patients undergoing either open or endovascular aneurysm repair had similar long-term survival at a median follow-up of over six years, despite an increased number of reinterventions in the endovascular repair group.1 The apparent short-term benefits in 30-day operative mortality with EVAR disappeared within the two-year analysis of the DREAM trial.2 However, the immediate advantage of endovascular repair cannot be negated and is reflected in the quality of life after endovascular repair when compared to open repair.3 Lower perioperative mortality, short term quality of life advantage, reduced endograft durability and ongoing surveillance after endovascular repair are important matters to discuss with patients. Endograft surveillance is mandatory after EVAR, because of the risk of endoleak and endograft failure.4, 5 There is much discussion in Europe and in the United Kingdom (UK) regarding when and how surveillance should be undertaken.4, 6, 7 Although endovascular repair is associated with a higher re-intervention rate, it does not translate into a long-term disadvantage in overall survival. The risks associated with reinterventions and endoleak need to be assessed in larger studies, particularly with regards to the influence on health-related quality of life.3 In theory, the inferior durability of endovascular repair when compared with open repair could influence longer-term survival outcomes and attenuate the short-term survival benefits of endovascular repair, or even result in increased longer-term risk. Our recent manuscript regarding this issue did not show any negative effects of inferior durability resulting in decreased survival.8 However, the UK counterpart of this randomised trial (EVAR 1 trial) has published a 15-years follow-up of their patients and found that endovascular repair is associated with inferior late survival, warranting lifelong surveillance of patients treated by endovascular means.9 Divergence of the survival curves in the EVAR-1 study population can only be partly explained through aneurysm-related deaths in the EVAR group.9 The analysis of this trial shows a significant difference at late follow up between endovascular and open aneurysm repair. By this time the number of patients at risk has dropped significantly, and this will have influenced the reliability of these results, especially while both studies were powered to detect short and mid-term differences.10, 11 Therefore, questions arise as to whether a robust conclusion can be drawn from analysing this time-period separately, rather than using normal Kaplan-Meier survival analysis. Overall survival at this time-period is not significantly different when analysing our own trial results after 12 to 15 years of follow-up.8 In our study, reinterventions undertaken more than four years after aneurysm repair were indicated because of endograft migration, limb thrombosis, or endoleak.1 One case involving reintervention for an endograft limb occlusion was followed by death a few days later, illustrating how reinterventions can increase the risk of aneurysm related

94 | CHAPTER 8

death.1 Despite this concern, graft-related complications and aneurysm ruptures were not frequent causes of death. 1, 8

Continuous development of endografts, imaging techniques and pre-operative planning results in better application of endovascular aneurysm treatment. 12-19 Durability will increase with progression of technology. First generation stentgrafts lacked proximal fixation causing migration and type 1 endoleaks. 20 With better understanding of type 2 endoleaks, the need for reintervention regarding this finding has dropped significantly reducing the reintervention rate in endovascular treated patients. 21 Due to the advent of fenestrated grafts shorter or larger aortic necks will not be treated with an infrarenal graft, but with custom-made fenestrated stentgrafts with a better sealing zone and reduced risk of type 1 endoleak. 22, 23 While percutaneous techniques have resulted in shorter hospital stay and fewer groin related complications, this will further positively influence the costs of endovascular procedures and will lead to short-stay EVAR programs. 24, 25

The majority of deaths recorded in our trial were either due to cardiovascular causes or cancer. 1 Therefore, cardiovascular risk modification has the potential to increase long-term survival in these patients. The DREAM trial started enrolling patients in 2000, at which time statins were not considered mandatory in cardiovascular risk management of AAA patients in The Netherlands. In our study we showed statin therapy to be independently associated with better long-term survival after open or endovascular aneurysm repair. 26 Other factors influencing survival in our population were advancing age, cardiac disease, and tobacco use. It is noted that the study was not designed to detect a difference in survival rates between patients with or without lipid- lowering medication. We adjusted for a number of potential confounders in the multivariable analyses, however residual confounding cannot be excluded. Improving the cardiovascular risk profile with intensive vascular counselling and optimal cardio-protective medication can play a key role in sustaining the beneficial effect of endovascular aneurysm repair postoperatively. 26 Supporting this, three recent publications demonstrate the potential benefit with respect to long-term survival after open and endovascular aneurysm repair from adequate cardiovascular risk management. 27-29

The cluster of reinterventions that appeared in the fifth year after endovascular repair is particularly troubling and casts doubt on the durability of endovascular devices.1 All the randomised trials comparing open with endovascular aneurysm repair have shown that graft-related complications and secondary intervention are common after EVAR. 1, 30, 31

The limitation of both the DREAM and EVAR trials is that both studies started recruiting over 15 years ago; 2, 32 and newer devices have been developed to address issues with earlier devices and graft-related complications. Recent registry data demonstrates

8


that despite evolutions in practice and devices, reinterventions remain a concern after EVAR and can be predicted by the SGVI score, as used in our study. 4, 33, 34 To investigate which factors are associated with a higher reintervention rate, we used pre-operative morphological features to predict the risk of reintervention. Our analysis showed a clear association between the SGVI score and reintervention risk.4 The SGVI score was predictive of reintervention for EVAR and open AAA repair. This score incorporates aneurysm and iliac diameter and formalizes their relationship with reintervention in a risk score that is easy to use for practicing clinicians.32 The SGVI score might be used to better inform patient selection in the preoperative consent process. One alternative application for the SGVI score may lie in the stratification of surveillance imaging after EVAR; for instance, with intensified surveillance for patients with adverse morphologic features. Further research should address the hypothesis of whether risk-stratified surveillance after EVAR, and intensifying follow-up for patients at risk after aneurysm repair, can fulfil the dual aims of improving the cost-effectiveness of the procedure without jeopardising long-term safety. 35 Against a background of increasing life expectancy and the ongoing debate around whether or not to treat young and low-risk patients with EVAR, long-term durability is of utmost importance. 8, 9 Furthermore a recent study show that reintervention after endovascular aneurysm repair remains an important issue. 36

Another factor that might influence long-term outcomes is progression of disease in the aortic neck after aneurysm treatment. In order to investigate the proportion of the neck that was left untreated after both open and endovascular repair, we compared residual neck length, determined by computed tomography scans among our patients. We demonstrated that after open repair, a longer segment of infrarenal neck is left untreated than after EVAR. 37 The length of this residual infrarenal neck after aortic repair was vastly underestimated by most surgeons in our study. 37 It enrolled a selective group of patients with long infrarenal necks as they were all considered suitable for EVAR. One might argue that current open repair patients all lack a suitable neck and that juxtarenal aneurysm repair is more appropriate in these patients. The findings presented here indicate that placement of a clamp at the infrarenal neck leaves at least one centimetre of native aorta in situ, that may be prone to further dilatation. Theoretically, the untreated segment can have a negative impact on the long-term durability of open repair, by degradation of this infrarenal neck leading to new or para-anastomotic aneurysm formation. 38-41 Conversely, despite full coverage of the infrarenal neck, endoleak and endograft migration can occur after EVAR, particularly with continuing dilatation of this infrarenal aortic segment. 42-46

Since the introduction of the endovascular technique, renal function after aneurysm repair has been a concern. Renal failure is a major public health problem associated

96 | CHAPTER 8

with high costs, poor outcomes 47-49, and impaired survival especially after vascular surgery. 50-53 During EVAR, renal dysfunction is of specific concern owing to the administration of nephrotoxic contrast agents and instrumentation in the juxtarenal aorta. Contrast induced nephropathy is a significant complication of radiographic contrast administration, which represents the third leading cause of hospital-acquired renal insufficiency. 54 However, the more invasive nature of open aneurysm repair may pose a risk of renal dysfunction directly after surgery. 55, 56

The estimated glomerular filtration rate (eGFR) of patients in our trial declined after five years of follow-up and is similar to that recorded in the first three years of the EVAR 1 trial. 57, 58 Neither study found any difference in renal function between EVAR and open repair. Consistent findings in these two independent cohorts provide some reassurance as to the validity of our results. Compared with large population-based studies, patients in the DREAM trial had lower preoperative mean eGFR than their age-matched, healthier counterparts. 59 However, the subsequent decline in their eGFR over time is in accordance with findings in the general population. 59, 60 A subset of patients remain at greater risk of deteriorating renal function after AAA repair, especially those with more advanced pre-existing renal impairment. 53, 61-63 These patients have higher morbidity and mortality rates than those with relatively normal renal function. 50-53 No conclusions about the effects of open repair and EVAR on renal function can be drawn for patients with more advanced kidney disease, while this was one of the exclusion criteria of the DREAM trial.

Morbidity and mortality are well-established measures of surgical outcomes as the paragraphs above illustrate. However, in line with patient-centered health care, more subjective measures, such as Quality of Life (QoL) and Health Status (HS) are increasingly important. In our trial, deterioration in QoL occurred early after surgical intervention, especially in the physical domains of SF-36®. 64 A significant difference was observed in several of the predominantly physical domains of SF-36® between the endovascular and open repair group at early intervals (≤6 weeks) in favour of EVAR. Subsequently, open repair was favoured at late follow-up (≥ 3 months). 64 This significant long-term difference between open and endovascular repair, favoured open repair in several domains of SF-36® and in EQ-5D™. 64 Lifelong surveillance following EVAR may, however, influence long-term outcomes and possibly account for some of the sustained differences in the measures reported here. This influence may be a result of the burden of surveillance in long-term follow-up, which is considerable. Despite this, the perioperative benefit of EVAR in terms of primary and secondary outcome parameters such as mortality, complications and hospital stay cannot be ignored. Patient-reported outcomes are becoming increasingly important in clinical medicine, especially in view of decreasing morbidity and mortality rates. Mortality and morbidity rate should therefore, not be

8


the only criteria for assessing treatment success. 65, 66 Patient-reported outcomes could have an impact on choice of the appropriate intervention, especially if mortality rates for these two treatment strategies are equivalent. 65 Accordingly, information on the anticipated effects of different treatment strategies on QoL should be shared with patients and the feasibility of doing so has been demonstrated.66, 67 The development of validated tools to measure disease-specific outcomes after aortic aneurysm surgery may also go some way to improving understanding of the impact of such interventions on this group of elderly patients. 68, 69

In the face of long-term survival being similar in both groups, the importance of the short-term benefits for patients following EVAR cannot be overstated. We should target our efforts towards improving Quality of Life, refining the application and indication for this technique. As such, we should identify how to approach surveillance after endovascular repair including improving the durability of our devices and improve cost-effectiveness.

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List of publications

Dankwoord

Curriculum Vitae

LIST OF PUBLICATIONS | 105

LIST OF PUBLICATIONS

• Shaw SE, Preece R, Stenson KM, de Bruin JL, Loftus IM, Holt PJE, Patterson BO. Short Stay EVAR is Safe and Cost Effective. Eur J Vasc Endovasc Surg. 2019 Mar;57(3):368-373.

• Stenson KM, Patterson BO, Grima MJ, de Bruin JL, Holt PJE, Loftus I. Midterm results of endovascular aneurysm sealing to treat abdominal aortic aneurysm. J Vasc Surg. 2019 Jan;69(1):53-62.e1.

• Stenson K, Patterson B, Grima MJ, de Bruin J, Holt P, Loftus I. Endovascular aneurysm sealing with chimney grafts to treat juxtarenal and suprarenal abdominal aortic aneurysms: Early results from 62 cases. J Vasc Surg. 2018 Dec 21.

• Patterson BO, Stenson K, Grima M, de Bruin J, Al-Subaie N, Loftus IM, Thompson MM, Holt PJ. Postoperative Complications Decrease Long-Term Survival After Thoracic Aneurysm Repair Despite Apparently Successful “Rescue” From Early Mortality. Circulation. 2018 Feb 6;137(6):636-638.

• D’Abate F, Oladokun D, La Leggia A, Hinchliffe R, Thompson M, Holt P, de Bruin J, Loftus I, Patterson B. Transthoracic Ultrasound Evaluation of Arch and Descending Thoracic Aortic Pathology. Eur J Vasc Endovasc Surg. 2018 May;55(5):658-665.

• D’Abate F, de Bruin JL. Additional value of B-flow imaging in arterial wall calcifications. J Clin Ultrasound. 2018 Feb;46(2):136-139

• van Schaik TG, Yeung KK, Verhagen HJ, de Bruin JL, van Sambeek MRHM, Balm R, Zeebregts CJ, van Herwaarden JA, Blankensteijn JD; DREAM trial participants. Long-term survival and secondary procedures after open or endovascular repair of abdominal aortic aneurysms. J Vasc Surg. 2017 Nov;66(5):1379-1389

• Oladokun D, Patterson BO, Brownrigg JR, deBruin JL, Holt PJ, Loftus I, Thompson MM. Early outcomes after left subclavian artery revascularisation in association with thoracic endovascular aortic repair. Vascular. 2017 Feb;25(1):74-79.

• Stenson KM, de Bruin JL, Holt PJ, Loftus IM, Thompson MM. Extended use of endovascular aneurysm sealing: Chimneys for juxtarenal aneurysms. Semin Vasc Surg. 2016 Sep;29(3):120-125

• De Bruin JL, Brownrigg JR, Patterson BO, Karthikesalingam A, Holt PJ, Hinchliffe RJ, Loftus IM, Thompson MM. The Endovascular Sealing Device in Combination with Parallel Grafts for Treatment of Juxta/Suprarenal Abdominal Aortic Aneurysms: Short-term Results of a Novel Alternative. Eur J Vasc Endovasc Surg. 2016 Oct;52(4):458-465.

• De Bruin JL, Groenwold RH, Baas AF, Brownrigg JR, Prinssen M, Grobbee DE, Blankensteijn JD; DREAM Study Group. Quality of life from a randomized trial of open and endovascular repair for abdominal aortic aneurysm. Br J Surg. 2016 Jul;103(8):995-1002.

106 | LIST OF PUBLICATIONS

• De Bruin JL, Karthikesalingam A, Holt PJ, Prinssen M, Thompson MM, Blankensteijn JD; Dutch Randomised Endovascular Aneurysm Management (DREAM) Study Group. Predicting reinterventions after open and endovascular aneurysm repair using the St George’s Vascular Institute score. J Vasc Surg. 2016 Jun;63(6):1428-1433.e1.

• Reijnen MM, de Bruin JL, Mathijssen EG, Zimmermann E, Holden A, Hayes P, Krievins D, Böckler D, de Vries JP, Thompson MM. Global Experience With the Nellix Endosystem for Ruptured and Symptomatic Abdominal Aortic Aneurysms. J Endovasc Ther. 2016 Feb;23(1):21-8.

• Bahia SS, de Bruin JL. Long-Term Renal Function after Abdominal Aortic Aneurysm Repair. Clin J Am Soc Nephrol. 2015 Nov 6;10(11):1889-91.

• Karthikesalingam A, de Bruin JL, Patel SR, Azhar B, Rossi L, Morgan RA, Holt PJ, Loftus IM, Thompson MM. Appearance of the Nellix endovascular aneurysm sealing system on computed tomography: implications for postoperative imaging surveillance. J Endovasc Ther. 2015 Jun;22(3):297-302.

• De Bruin JL, Brownrigg JR, Karthikesalingam A, Patterson BO, Holt PJ, Hinchliffe RJ, Morgan RA, Loftus IM, Thompson MM. Endovascular aneurysm sealing for the treatment of ruptured abdominal aortic aneurysms. J Endovasc Ther. 2015 Jun;22(3):283-7.

• Brownrigg JR, de Bruin JL, Rossi L, Karthikesalingam A, Patterson B, Holt PJ, Hinchliffe RH, Morgan R, Loftus IM, Thompson MM. Endovascular aneurysm sealing for infrarenal abdominal aortic aneurysms: 30-day outcomes of 105 patients in a single centre. Eur J Vasc Endovasc Surg. 2015 Aug;50(2):157-64

• Hughes CO, de Bruin JL, Karthikesalingam A, Holt PJ, Loftus IM, Thompson MM. Management of a type Ia endoleak with the Nellix endovascular aneurysm sealing system. J Endovasc Ther. 2015 Jun;22(3):309-11.

• D’Abate F, Harrison SA, Karthikesalingam A, de Bruin J, Hinchliffe RJ, Loftus IM, Holt PJ, Morgan RA, Thompson MM. Sonographic appearance following endovascular aneurysm repair using the Nellix endovascular sealing system. J Endovasc Ther. 2015 Apr;22(2):182-6.

• Karthikesalingam A, Vidal-Diez A, de Bruin JL, Thompson MM, Hinchliffe RJ, Loftus IM, Holt PJ. International validation of a risk score for complications and reinterventions after endovascular aneurysm repair. Br J Surg. 2015 Apr;102(5):509-15.

• Malkawi AH, de Bruin JL, Loftus IM, Thompson MM. Treatment of a juxtarenal aneurysm with the Nellix endovascular aneurysm sealing system and chimney stent. J Endovasc Ther. 2014 Aug;21(4):538-40.

• Niepoth WW, de Bruin JL, Lely RL, Wisselink W, de Vries JP, Yeung KK, Blankensteijn JD. In vitro feasibility of a sac-sealing endoprosthesis in a double chimney graft configuration for juxtarenal aneurysm. J Endovasc Ther. 2014 Aug;21(4):529-37.

LIST OF PUBLICATIONS | 107

• Patterson B, de Bruin JL, Brownrigg JR, Holt PJ, Loftus IM, Thompson MM, Hinchliffe RJ. Current endovascular management of acute type B aortic dissection - whom should we treat and when? J Cardiovasc Surg (Torino). 2014 Aug;55(4):491-6.

• van Tol EN, de Bruin JL, Blankensteijn JD. Treatment of abdominal aortic aneurysm: is there still a place for open repair? Ned Tijdschr Geneeskd. 2014;158:A6994

• De Bruin JL, Baas AF, Heymans MW, Buimer MG, Prinssen M, Grobbee DE, Blankensteijn JD; DREAM Study Group. Statin therapy is associated with improved survival after endovascular and open aneurysm repair. J Vasc Surg. 2014 Jan;59(1):39-44.e1.

• De Bruin JL, Vervloet MG, Buimer MG, Baas AF, Prinssen M, Blankensteijn JD; DREAM Study Group. Renal function 5 years after open and endovascular aortic aneurysm repair from a randomized trial. Br J Surg. 2013 Oct;100(11):1465-70.

• Niepoth WW, de Bruin JL, Yeung KK, Lely RJ, Devrome AN, Wisselink W, Blankensteijn JD. A proof-of-concept in vitro study to determine if EndoAnchors can reduce gutter size in chimney graft configurations. J Endovasc Ther. 2013 Aug;20(4):498-505.

• De Bruin JL, Yeung KK, Niepoth WW, Lely RJ, Cheung Q, de Vries A, Blankensteijn JD. Geometric study of various chimney graft configurations in an in vitro juxtarenal aneurysm model. J Endovasc Ther. 2013 Apr;20(2):184-90.

• Konings R, de Bruin JL, Wisselink W. Open fenestration of the distal landing zone via a subxyphoid incision for subsequent endovascular repair of a dissecting thoracic aneurysm. J Endovasc Ther. 2013 Feb;20(1):28-31.

• Vos CG, de Bruin JL, Wisselink W. A woman with palpitations and dysphagia. Ned Tijdschr Geneeskd. 2013;157(4):A5063

• Blankensteijn JD, de Bruin JL, Baas AF. Decision making in AAA repair in 2012: open or endo? J Cardiovasc Surg (Torino). 2012 Feb;53(1 Suppl 1):101-9.

• De Bruin JL, de Jong S, Pol J, van der Jagt M, Prinssen M, Blankensteijn JD. Residual infrarenal aortic neck following endovascular and open aneurysm repair. Eur J Vasc Endovasc Surg. 2012 Apr;43(4):415-8

• De Bruin JL, Baas AF, Buth J, Prinssen M, Verhoeven EL, Cuypers PW, van Sambeek MR, Balm R, Grobbee DE, Blankensteijn JD; DREAM Study Group. Long-term outcome of open or endovascular repair of abdominal aortic aneurysm. N Engl J Med. 2010 May 20;362(20):1881-9.

• Arai T, Kofidis T, Bulte JW, de Bruin J, Venook RD, Berry GJ, Mcconnell MV, Quertermous T, Robbins RC, Yang PC. Dual in vivo magnetic resonance evaluation of magnetically labeled mouse embryonic stem cells and cardiac function at 1.5 t. Magn Reson Med. 2006 Jan;55(1):203-9.

108 | LIST OF PUBLICATIONS

• Kofidis T, deBruin JL, Tanaka M, Zwierzchoniewska M, Weissman I, Fedoseyeva E, Haverich A, Robbins RC. They are not stealthy in the heart: embryonic stem cells trigger cell infiltration, humoral and T-lymphocyte-based host immune response. Eur J Cardiothorac Surg. 2005 Sep;28(3):461-6.

• Swijnenburg RJ, Tanaka M, Vogel H, Baker J, Kofidis T, Gunawan F, Lebl DR, Caffarelli AD, de Bruin JL, Fedoseyeva EV, Robbins RC. Embryonic stem cell immunogenicity increases upon differentiation after transplantation into ischemic myocardium. Circulation. 2005 Aug 30;112(9 Suppl):I166-72.

• Tanaka M, Swijnenburg RJ, Gunawan F, Cao YA, Yang Y, Caffarelli AD, de Bruin JL, Contag CH, Robbins RC. In vivo visualization of cardiac allograft rejection and trafficking passenger leukocytes using bioluminescence imaging. Circulation. 2005 Aug 30;112(9 Suppl):I105-10.

• Kofidis T, de Bruin JL, Hoyt G, Ho Y, Tanaka M, Yamane T, Lebl DR, Swijnenburg RJ, Chang CP, Quertermous T, Robbins RC. Myocardial restoration with embryonic stem cell bioartificial tissue transplantation. J Heart Lung Transplant. 2005 Jun;24(6):737-44.

• Kofidis T, de Bruin JL, Yamane T, Tanaka M, Lebl DR, Swijnenburg RJ, Weissman IL, Robbins RC. Stimulation of paracrine pathways with growth factors enhances embryonic stem cell engraftment and host-specific differentiation in the heart after ischemic myocardial injury. Circulation. 2005 May 17;111(19):2486-93.

• Kofidis T, de Bruin JL, Yamane T, Balsam LB, Lebl DR, Swijnenburg RJ, Tanaka M, Weissman IL, Robbins RC. Insulin-like growth factor promotes engraftment, differentiation, and functional improvement after transfer of embryonic stem cells for myocardial restoration. Stem Cells. 2004;22(7):1239-45.

• Kofidis T, de Bruin JL, Hoyt G, Lebl DR, Tanaka M, Yamane T, Chang CP, Robbins RC. Injectable bioartificial myocardial tissue for large-scale intramural cell transfer and functional recovery of injured heart muscle. J Thorac Cardiovasc Surg. 2004 Oct;128(4):571-8.

• Kofidis T, Balsam L, de Bruin J, Robbins RC. Distinct cell-to-fiber junctions are critical for the establishment of cardiotypical phenotype in a 3D bioartificial environment. Med Eng Phys. 2004 Mar;26(2):157-63.

DANKWOORD | 109

DANKWOORD

Mijn naam staat misschien op de kaft van dit boekje, echter zonder de hulp en steun van vele anderen was dit nooit voltooid. Helaas heb ik de zelf de andere kant van het ziekbed kunnen ervaren. Daarom wil ik allereerst alle patiënten die hen lot aan randomisatie en deze studie hebben verbonden bedanken. Dit vormt de basis van dit proefschrift en het wetenschappelijk bewijs voor wat we elke week als vaatchirurg doen; het endovasculair herstellen van een aneurysma.

Alle chirurgen en radiologen die hebben meegewerkt aan DREAM trial wil ik ook vermelden voor hun samenwerking en inzet, ik voelde me zeer welkom als ik op bezoek kwam in de individuele ziekenhuizen die hebben meegewerkt aan deze studie en iedereen was zeer behulpzaam.

Prof. Blankensteijn, beste Jan, ik voel me zeer bevoorrecht door jou wetenschappelijk en klinisch te zijn opgeleid. Ik heb zoveel geleerd wat ik dagelijks kan gebruiken; het omgaan met patiënten, het nauwkeurig lezen van een CT, opereren en het doen van wetenschappelijk onderzoek. Daarnaast ben je altijd zeer bescheiden ondanks je zeer geroemde reputatie. Je bent het ultieme voorbeeld voor mij!

Prof. Grobbee, het feit dat DREAM ON heeft kunnen profiteren van uw kennis en van de professionaliteit van het Julius Centrum maakt dit proefschrift mogelijk. Uw wetenschappelijk inzicht straalt af van het zeer goede commentaar op onze manuscripten.

Monique Prinssen, copromotor, zonder jou was er geen DREAM trial en ik ben je dan ook zeer dankbaar voor het feit dat ik jouw werk mocht voortzetten.

Annette Baas, je goede hulp en inzet voor DREAM-on en het me wegwijs maken op het Julius Centrum. Je hebt me zeer goed op weg geholpen en ben je zeer dankbaar.

Nicole Boekema, alle data en bestanden waren altijd perfect georganiseerd. Je was altijd bereikbaar en hebt ons vele jaren goed geholpen.

Veel dank aan de leden van de leescommissie, prof Wisselink, prof Schurink, prof Legemate, prof Boer, prof Loftus voor de bereidheid mijn manuscript te beoordelen en te voorzien van commentaar.

110 | DANKWOORD

Dr Vriens, Patrick, zonder jou was ik nooit naar Amerika gegaan, dit was een geweldige kans en heeft me naast het werk op Stanford enorm leuke ervaringen opgeleverd. Ik ben je ook zeer dankbaar voor het geduld dat je had tijdens mijn opleiding. Je bent een geboren opleider en ik kijk met veel plezier terug op mijn differentiatiejaar in Tilburg.

Dr van Berge Henegouwen, Dennis, ik heb super veel in mijn eerste jaren van mijn opleiding geleerd van jou. Ik zal altijd met veel plezier terugdenken aan onze eerste wintersportreis in jouw jaguar (2x!). We voelden ons bevoorrecht dat we de laatste keer in je gloednieuwe jaguar naar Frankrijk mochten rijden! Dank voor de goede tijden en introductie bij de AIVS.

Ook de overige chirurgen uit het Elisabeth Ziekenhuis en het Radboud Ziekenhuis en collega arts-assistenten wil ik danken voor de goede tijd die we hebben gehad. Het was een zeer gedegen opleiding en denk nog vaak terug aan de goede sfeer in de assistentengroep en de leuke ski-uitjes die we hebben gehad.

Prof Wisselink, Willem, je bent een enorm pietje precies en je kan zeer duidelijk verwoorden hoe je denkt dat het op de operatiekamer moet. Ik heb enorm veel van je geleerd en heb nog steeds een papiertje op mijn bureau waar ik met 8.0 prolene op oefen.

Beste Hoks, Hillian, Hans en prof Rauwerda enorm bedankt voor jullie goede begeleiding in de VU, jullie hebben een vaatchirurg van me gemaakt en daar ben ik jullie enorm dankbaar voor.

Dear colleagues in St George’s Hospital, London, at first I want to thank you for all the support you have given me throughout these years. It’s the perfect work-environment with excellent clinical results and it’s great being part of this world-class service. I feel privileged being part of our team. Dear Prof Loftus, thank you so much for joining us today and being part of this ceremony. I have learned a lot from you, Matt and Peter.Peter, Ian, Mox, Tom and Gary, thank you all so much during the difficult times I’ve had to endure, you have been very supportive and I am fortunate to have such caring colleagues. Dear Mr Chandrasekaran and Dr Sharma I would like to thank you both for saving my life and the excellent care you have provided, I will be eternally grateful. Obviously I would like to thank all the A&E, ITU and ward staff for their fabulous care as well!

DANKWOORD | 111

Rutger en Adriaan, enorm bedankt dat jullie hier als mijn paranimfen zijn, die tijden in het Leidsche lijken wel een eeuw geleden. Wat een supertijd was dat toch. Je ziet dat jullie enorme goede roeiersmentaliteit zich weerspiegelt in jullie professionele leven. Dank voor de steun toen ik ziek was, zowel professioneel als persoonlijk.

Evelijn, je bent een enorme steun voor ons gezin, en hebt me gaande gehouden. Je was altijd benieuwd naar de status van dit boekje.

Uiteraard wil ik mijn ouders bedanken voor alle liefde die ze me hebben gegeven en in mij hebben geïnvesteerd. Lieve pap en mam, super bedankt voor alle steun en blijvende steun bij vallen en opstaan….

Daarnaast wil ik mijn schoonouders bedanken, lieve Caia en JP. Dank voor alle steun ook in moeilijke tijden. Jullie zijn zulke goede ouders en grootouders, jullie zijn echt een voorbeeld voor mij.

Lieve, lieve Claire. Wat heb je me enorm gesteund, zonder jou was dit boekje nooit af geweest. Je hebt weer een enorm fijn thuis gemaakt in Nederland en ik ben je zeer dankbaar voor alle steun en liefde die je me geeft. Laura, Thomas en Felix jullie zijn geweldig en ik had me geen betere kinderen kunnen wensen. Jullie zorgen voor een dikke grijns op mijn gezicht en maken me intens gelukkig. Ik hoop nog lang van jullie te kunnen genieten!

112 | CURRICULUM VITAE

CURRICULUM VITAE

Jorg Lucas de Bruin was born on October 10, 1976 in Amsterdam, The Netherlands. After graduating from the Godelinde school, in Naarden he obtained his medical degree from the University of Leiden. During his studies, he spent ten months at Stanford Medical School in Palo Alto, USA, where he completed a research fellowship in cardiac surgery. Jorg combined medical school, with rowing on a national level. After stem-cell research in Stanford he started to work on the DREAM-trial with professor Blankensteijn. He finished his General Surgery residency at the St Elisabeth Hospital and St Radboud Hospital University Nijmegen and completed his Vascular Surgery training in Amsterdam at the VU. After a fellowship in Vascular Surgery at St George’s Hospital London, he was appointed as a Consultant Vascular Surgeon in 2014.

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Jorg Lucas de Bruin · prof.dr. V. Subramaniam, in het openbaar te verdedigen ten overstaan van de promotiecommissie van de Faculteit der Geneeskunde op vrijdag 7 juni 2019 om 13.45