comparison of outcomes in elective endovascular aortic

Original Investigation | Surgery

Comparison of Outcomes in Elective Endovascular Aortic Repairvs Open Surgical Repair of Abdominal Aortic AneurysmsKonrad Salata, MD; Mohamad A. Hussain, MD, PhD; Charles de Mestral, MD, PhD; Elisa Greco, MD, MEd; Badr A. Aljabri, MD; Muhammad Mamdani, PharmD, MPH, MA;Thomas L. Forbes, MD; Deepak L. Bhatt, MD, MPH; Subodh Verma, MD, PhD; Mohammed Al-Omran, MD, MSc

Abstract

IMPORTANCE Knowledge regarding the long-term outcomes of elective treatment of abdominalaortic aneurysm (AAA) using endovascular aortic repair (EVAR) is increasing. However, data withgreater than 10 years’ follow-up remain sparse and are lacking from population-based studies.

OBJECTIVE To determine the long-term outcomes of EVAR compared with open surgical repair(OSR) for elective treatment of AAA.

DESIGN, SETTING, AND PARTICIPANTS This retrospective, population-based cohort study usedlinked administrative health data from Ontario, Canada, to identify all patients 40 years and olderwho underwent elective EVAR or OSR for AAA repair from April 1, 2003, to March 31, 2016, withfollow-up terminating on March 31, 2017. A total of 17 683 patients were identified using validatedprocedure and billing codes and were propensity score matched. Analysis was conducted from June26, 2018, to January 16, 2019.

EXPOSURES Elective EVAR or OSR for AAA.

MAIN OUTCOMES AND MEASURES The primary outcome was overall survival. Secondaryoutcomes were major adverse cardiovascular event–free survival, defined as being free of death,myocardial infarction, or stroke; reintervention; and secondary rupture.

RESULTS Among 17 683 patients who received elective AAA repairs (mean [SD] age, 72.6 [7.8]years; 14 286 [80.8%] men), 6100 (34.5%) underwent EVAR and 11 583 (65.5%) underwent OSR.From these patients, 4010 well-balanced propensity score–matched pairs of patients were defined,with a mean (SD) age of 73.0 (7.6) years and 6583 (82.1%) men. In the matched cohort, the mean(SD) follow-up was 4.4 (2.7) years, and maximum follow-up was 13.8 years. The overall mediansurvival was 8.9 years. Compared with OSR, EVAR was associated with a higher survival rate up to 1year after repair (91.0% [95% CI, 90.1%-91.9%] vs 94.0% [95% CI, 93.3%-94.7%]) and a highermajor adverse cardiovascular event–free survival rate up to 4 years after repair (69.9% [95% CI,68.3%-71.3%] vs 72.9% [95% CI, 71.4%-74.4%]). Cumulative incidence of reintervention was higheramong patients who underwent EVAR compared with those who underwent OSR at the 7-yearfollow-up (45.9% [95% CI, 44.1%-47.8%] vs 42.2% [95% CI, 40.4%-44.0%]). Survival analysesdemonstrated no statistically significant differences in long-term survival, reintervention, andsecondary rupture for patients who underwent EVAR compared with those who underwent OSR.Kaplan-Meier analysis suggested superior long-term major adverse cardiovascular event–freesurvival among patients who underwent EVAR compared with those who underwent OSR (32.6%[95% CI, 26.9%-38.4%] vs 14.1% [95% CI, 4.0%-30.4%]; stratified log-rank P < .001) during amaximum follow-up of 13.8 years.

(continued)

Key PointsQuestion What are the long-term

outcomes of elective endovascular

aortic repair of abdominal aortic

aneurysms compared with those of

open surgical repair?

Findings In this population-based

cohort study including 17 683 patients

receiving elective treatment for

abdominal aortic aneurysms, no

statistically significant difference was

found in long-term all-cause mortality

between endovascular aortic repair and

open surgical repair during a maximum

follow-up of 13.8 years.

Meaning Endovascular aortic repair

was not associated with a long-term

survival benefit.

+ Supplemental content

Author affiliations and article information arelisted at the end of this article.

Open Access. This is an open access article distributed under the terms of the CC-BY License.

JAMA Network Open. 2019;2(7):e196578. doi:10.1001/jamanetworkopen.2019.6578 (Reprinted) July 10, 2019 1/14

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Abstract (continued)

CONCLUSIONS AND RELEVANCE Endovascular aortic repair was not associated with a differencein long-term survival during more than 13 years’ maximum follow-up. The reasons for these findingswill require studies to consider specific graft makes and models, adherence to instructions for use,and types and reasons for reintervention.

JAMA Network Open. 2019;2(7):e196578. doi:10.1001/jamanetworkopen.2019.6578

Introduction

Endovascular aortic repair (EVAR) has changed the landscape of abdominal aortic aneurysm (AAA)treatment since its introduction in 1991.1 Randomized and population-based studies investigatingEVAR vs open surgical repair (OSR) demonstrated superior perioperative survival as well assignificant improvements in operative time, blood loss, transfusion requirements, cardiopulmonarycomplications, and reduced lengths of stay in intensive care units and hospitals in favor of EVAR.2-4

Consequently, EVAR has seen rapid uptake and has become the predominant approach to AAAmanagement, as borne out by multiple Canadian,5 US,6,7 and European8 studies.

Despite its clear short-term superiority, early EVAR technology had unique complications,including endoleak, graft migration, graft thrombosis, and secondary rupture.9-12 Accordingly,patients who undergo EVAR require lifelong surveillance to identify and prevent these complications,and EVAR is associated with significantly higher reintervention rates.13 These are at least in partpostulated to be the reasons for the eventual loss of the EVAR mortality benefit demonstrated inEVAR randomized clinical trials (RCTs).14-17 However, since the inception of these trials in the 1990sand early 2000s, EVAR endografts have undergone numerous manufacturing reiterations to addressidentified endograft-related complications. As a result, the longevity of the mortality benefit ofcontemporary EVAR may be underestimated by these trials. On the other hand, limited data areavailable to elucidate whether EVAR is safe in the long term. Presently, the Endovascular AorticRepair 1 (EVAR-1) trial17 and Dutch Randomized Endovascular Aneurysm Management (DREAM)18

trial are the only trials to report longer than 10-year follow-up, and no population-based studies havebeen conducted with longer than 10 years of follow-up, to our knowledge.

This study aims to add to the limited literature regarding the long-term outcomes of EVAR.Specifically, the objective of this study is to assess the differences between EVAR and OSR forelective AAA repair in long-term survival, major adverse cardiovascular event (MACE)–free survival,reintervention, and secondary rupture. This developing body of knowledge will serve to betterdelineate the true mortality benefit of EVAR, considering accumulated experience, evolvedendografts, and better knowledge of complications and their appropriate management.

Methods

Study Design, Setting, and Data SourcesThe population of Ontario, Canada, is 14.2 million people. A retrospective, population-based cohortstudy of EVAR vs OSR for elective AAA management in Ontario, Canada, was performed usingadministrative health care data, in accordance with the Strengthening the Reporting of ObservationalStudies in Epidemiology (STROBE) reporting guideline for cohort studies. The Ontario Ministry of Healthand Long-Term Care records each publicly insured ambulatory, emergency, and inpatient health caresystem interaction requiring the use of an Ontario health card. The Institute for Clinical EvaluativeSciences, a prescribed entity governed under the Personal Health Information Protection Act, storesand manages these data. Data are linked together across primary sources using a unique encryptedidentifier known as the Institute for Clinical Evaluative Sciences key number. Ontario administrative dataare routinely used for population-level research and have previously been thoroughly described andvalidated.19-22 The specific databases used for this study are described in eTable 1 in the Supplement.

JAMA Network Open | Surgery Outcomes in Elective Endovascular Aortic Repair vs Open Surgical Repair of Abdominal Aortic Aneurysms




http://www.equator-network.org/reporting-guidelines/strobe/


This study was approved by the research ethics board at Sunnybrook Health Sciences Centre in Toronto,Ontario, Canada, and the requirement for informed consent was waived owing to the use of deidentifiedsecondary data.

Patient CohortAll elective EVARs and OSRs of AAA performed in Ontario, Canada, in patients 40 years and olderfrom April 1, 2003, to March 31, 2016, with maximum follow-up terminating on March 31, 2017, wereidentified. This age cutoff was used to reduce the likelihood of contamination with connective tissueaneurysms. Combinations of the International Statistical Classification of Diseases and Related HealthProblems, Tenth Revision, Canadian Revision; Canadian Classification of Health Intervention; andOntario Health Insurance Plan diagnostic, procedure, and billing codes were used according to apreviously validated algorithm.22 This algorithm identified EVAR (infrarenal) and OSR (infrarenal,pararenal, and juxtarenal) with 96% and 95% positive predictive values, respectively. Patients withmultiple AAA repair procedures listed on their index admission were excluded owing to an inability toestablish appropriate event chronology and, thus, the primary procedure. Patients who relocatedoutside of Ontario or whose health cards expired prior to study conclusion were also excluded.

CovariatesBaseline covariates included demographic characteristics, health care utilization, hospital andprocedure characteristics, comorbidities, medications, and tracer variables (used to helpdemonstrate absence of residual confounding). A full list of covariates, definitions, correspondingcodes, and references to respective validation studies is presented in eTable 2 in the Supplement. Allbaseline covariates were captured using a 5-year lookback window from the index procedure date,except those captured from the National Ambulatory Care Reporting System database, where a3-year lookback window was used, as this database commenced in July 2000. All medicationvariables, except for fluoroquinolones, were measured using a 4-month lookback window to assesswhether at least 1 prescription was recently filled, considering a 100-day maximum medicationdispensing limit. In the province of Ontario, patients younger than 65 years are not eligible forpublicly funded pharmaceutical care; as such, drug information is not captured for these individualswithin administrative data. Patients younger than 65 years without drug information were coded asineligible for the Ontario Drug Benefit program.

Outcomes and Follow-upThe primary outcome was overall survival. Secondary outcomes included MACE-free survival,defined as survival free of a composite of death, stroke, or myocardial infarction; any reintervention;and secondary rupture. These outcomes were defined according to previously validated codeswhere possible (eTable 2 in the Supplement). Patients were observed through administrativedatabases until the outcome of interest or end of the follow-up period on March 31, 2017, whicheverhappened first.

Statistical AnalysisA propensity score–matched survival analysis was performed.23,24 The propensity score for repairapproach was calculated using a logistic regression model incorporating all covariates as potentialconfounders. Patients who received EVAR or OSR were matched 1:1 using the greedy nearestneighbor method with a caliper width of 0.2 SD units. Balance of covariates was assessed usingstandardized differences, with differences less than 0.1 indicating good balance.25 Residualconfounding was assessed using the distribution of tracer variables not used to specify thepropensity score. Survival analyses were conducted using the Kaplan-Meier product limit method toassess differences in survival and MACE-free survival. Statistical differences were assessed using thestratified log-rank test with stratification on the matched pairs. To account for competing risks,cumulative incidence function analysis using a Fine and Gray model and stratified Gray test were






conducted to assess differences in reintervention and secondary rupture. Statistical significance wasset at a Bonferroni-corrected P value of 1.25 × 10−5 to adjust for the 4010 matched-paircomparisons.26,27 Survival and cumulative incidence rates and associated 95% CIs were obtainedfrom corresponding survival and cumulative incidence functions at 30 days, annually for up to 10years, as well as at maximum follow-up.

The calculated propensity score was used to conduct an inverse probability of treatment–weighted sensitivity analysis.28 The mean treatment effect in the treated weight was used, andbalance of covariates was assessed using standardized mean differences as well as variance ratios,with ratio values between 0.5 and 2.0 indicating good balance.29,30 Cox regression models with arobust sandwich variance estimator were then used to calculate hazard ratios (HRs) for each of theoutcomes.31 Cause-specific Cox models were fit for the reintervention and secondary ruptureoutcomes to account for competing risks. Proportionality of hazards was investigated using log-logsurvival plots and time-dependent covariates. Where hazards were not proportional, data werepartitioned into multiple time intervals, and separate Cox models were built for each interval. Cutoffvalues were determined using plots of Schoenfeld residuals through time and tested as previouslydescribed. Statistical significance was set at a 2-tailed P value less than .05. All statistical analyseswere conducted in SAS statistical software version 9.4 (SAS Institute). Analysis was conducted fromJune 26, 2018, to January 16, 2019.

Results

Cohort CharacteristicsThe overall study population consisted of 17 683 patients who received elective AAA repairs (mean[SD] age, 72.6 [7.8] years; 14 286 [80.8%] men). Of these patients, 6100 (34.5%) underwent EVARand 11 583 (65.5%) underwent OSR (Table). In the overall cohort, patients who underwent EVARwere more likely to be older, be men, reside in areas with populations more than 10 000 people, anduse the health care system more frequently. Furthermore, patients who underwent EVAR were morelikely to have comorbid congestive heart failure, diabetes, hypertension, and a Charlson ComorbidityIndex score of 2 or more, while patients who underwent OSR were more likely to have underlyingperipheral arterial disease. Patients older than 65 years who underwent EVAR were more likely to beprescribed statin, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker,anticoagulant, or noninsulin antidiabetes medications or prednisone and were more likely to have ahistory of fluoroquinolone use. Additionally, EVAR procedures within the unmatched cohort weremore commonly conducted in teaching hospitals or high-volume hospitals (defined as �10 AAAprocedures per year) and were more common than OSR after 2009. The propensity matched–cohortincluded 4010 pairs of patients (mean [SD] age, 73.0 [7.6] years; 6583 [82.1%] men) who underwentEVAR or OSR and did not demonstrate any significant differences in baseline covariates or tracervariables.

OutcomesMean (SD) follow-up for the entire cohort was 5.5 (3.6) years with a maximum follow-up of 14.0years. Among the matched cohort, mean (SD) follow-up was 4.4 (2.7) years with a maximumfollow-up of 13.8 years. Median survival for the unmatched cohort was 9.4 years overall, 7.8 yearsamong patients who underwent EVAR, and 9.8 years among patients who underwent OSR. In thematched cohort, median survival was 8.9 years overall and in each treatment group.

Within the matched cohort, EVAR was associated with a higher survival rate than OSR for up to1 year after repair (94.0% [95% CI, 93.3%-94.7%] vs 91.0% [95% CI, 90.1%-91.9%]), and a higherMACE-free survival rate for up to 4 years after repair (72.9% [95% CI, 71.4%-74.4%] vs 69.9% [95%CI, 68.3%-71.3%]) (eTable 3 in the Supplement). The cumulative incidence of reintervention within30 days was lower among patients who underwent EVAR compared with OSR (12.4% [95% CI, 11.4%-13.5%] vs 15.0% [95% CI, 13.9%-16.1%]) but higher after 7 years (45.9% [95% CI, 44.1%-47.8%] vs





Table. Baseline Characteristics of Unmatched and Propensity Score–Matched Cohorts

Variable

Unmatched Cohort Matched Cohort

No. (%)StandardizedDifference

No. (%)StandardizedDifferenceEVAR (n = 6100) OSR (n = 11 583) EVAR (n = 4010) OSR (n = 4010)

Demographic Characteristics

Age, mean (SD), y 75.3 (7.9) 71.2 (7.8) 0.52 73.1 (7.7) 72.8 (7.4) 0.03

Men 5159 (84.6) 9127 (78.8) 0.15 3310 (82.5) 3273 (81.6) 0.02

Income quintile

1 (Lowest) 1135 (18.6) 2342 (20.2) 0.04 753 (18.8) 758 (18.9) 0

2 1304 (21.4) 2517 (21.7) 0.01 849 (21.2) 851 (21.2) 0

3 1166 (19.1) 2276 (19.6) 0.01 803 (20.0) 788 (19.7) 0.01

4 1260 (20.7) 2306 (19.9) 0.02 823 (20.5) 814 (20.3) 0.01

5 (Highest) 1226 (20.1) 2102 (18.1) 0.05 774 (19.3) 790 (19.7) 0.01

Not reported 9 (0.1) 40 (0.3) 0.04 8 (0.2) 9 (0.2) 0.01

Rural residence 922 (15.1) 2244 (19.4) 0.11 691 (17.2) 700 (17.5) 0.01

Health care utilization, mean (SD), No.

Outpatient physician visits within 1 y 14.4 (8.2) 13.4 (7.5) 0.12 13.6 (7.5) 13.4 (7.7) 0.02

Emergency department visitswithin 3 y

2.4 (3.8) 1.9 (3.0) 0.14 2.1 (3.5) 2.1 (3.4) 0.01

Hospital admissions within 3 y 0.8 (1.3) 0.7 (1.1) 0.15 0.7 (1.2) 0.7 (1.2) 0.02

Comorbidities

Charlson Comorbidity Index score

0 902 (14.8) 1592 (13.7) 0.03 571 (14.2) 579 (14.4) 0.01

1 916 (15.0) 1846 (15.9) 0.03 607 (15.1) 627 (15.6) 0.01

≥2 1605 (26.3) 2104 (18.2) 0.20 876 (21.8) 856 (21.3) 0.01

Not reported 2677 (43.9) 6041 (52.2) 0.17 1956 (48.8) 1948 (48.6) 0

Coronary artery disease 1082 (17.7) 1957 (16.9) 0.02 672 (16.8) 668 (16.7) 0

Myocardial infarction 373 (6.1) 640 (5.5) 0.03 223 (5.6) 219 (5.5) 0

Congestive heart failure 1082 (17.7) 1183 (10.2) 0.22 527 (13.1) 497 (12.4) 0.02

Peripheral artery disease 169 (2.8) 1567 (13.5) 0.40 131 (3.3) 132 (3.3) 0

Cerebrovascular disease 78 (1.3) 191 (1.6) 0.03 61 (1.5) 60 (1.5) 0

Stroke or transient ischemic attack 226 (3.7) 401 (3.5) 0.01 131 (3.3) 141 (3.5) 0.01

Diabetes 1877 (30.8) 2711 (23.4) 0.17 1172 (29.2) 1148 (28.6) 0.01

Hypertension 5025 (82.4) 8944 (77.2) 0.13 3243 (80.9) 3228 (80.5) 0.01

Chronic obstructive pulmonary disease 2530 (41.5) 4247 (36.7) 0.10 1614 (40.2) 1575 (39.3) 0.02

Chronic kidney disease 161 (2.6) 197 (1.7) 0.06 89 (2.2) 71 (1.8) 0.03

Prior procedure

Coronary revascularization 700 (11.5) 1234 (10.7) 0.03 461 (11.5) 453 (11.3) 0.01

Peripheral revascularization 1276 (20.9) 2694 (23.3) 0.06 815 (20.3) 841 (21.0) 0.02

Major amputation 1-5a 14 (0.1) 0.03 1-5a 1-5a 0.03

Carotid revascularization 72 (1.2) 192 (1.7) 0.04 57 (1.4) 55 (1.4) 0

Medication

Statins 3712 (60.9) 5889 (50.8) 0.20 2336 (58.3) 2317 (57.8) 0.01

β-Blockers 2208 (36.2) 3903 (33.7) 0.05 1359 (33.9) 1333 (33.2) 0.01

Angiotensin-converting enzymeinhibitors or angiotensinreceptor blockers

3279 (53.8) 5355 (46.2) 0.15 2046 (51.0) 2024 (50.5) 0.01

Antiplatelets 6 (0.1) 31 (0.3) 0.04 6 (0.1) <6a 0.01

Anticoagulants 750 (12.3) 696 (6.0) 0.22 353 (8.8) 336 (8.4) 0.02

Fluoroquinolones 543 (8.9) 703 (6.1) 0.11 303 (7.6) 289 (7.2) 0.01

Antidiabetics 774 (12.7) 1012 (8.7) 0.13 485 (12.1) 468 (11.7) 0.01

Prednisone 328 (5.4) 336 (2.9) 0.12 166 (4.1) 162 (4.0) 0.01

Insulin 122 (2.0) 112 (1.0) 0.09 72 (1.8) 66 (1.6) 0.01

Ontario drug benefit–eligible 5469 (89.7) 9196 (79.4) 0.29 3432 (85.6) 3390 (84.5) 0.03

(continued)




42.2% [95% CI, 40.4%-44.0%]) (eTable 3 in the Supplement). No significant differences in thecumulative incidence of secondary rupture were demonstrated within the matched cohort atmaximum follow-up (EVAR, 1.5% [95% CI, 0.9%-2.5%]; OSR, 0.8% [95% CI, 0.6%-1.2%]) (eTable 3in the Supplement).

Kaplan-Meier survival analysis demonstrated no statistically significant differences betweenEVAR and OSR in long-term survival (at maximum follow-up: EVAR, 41.5% [95% CI, 37.7%-45.2%];OSR, 26.9% [95% CI, 15.7%-39.5%]; stratified log-rank P = .004) (Figure 1). However, EVAR wasassociated with superior long-term MACE-free survival (at maximum follow-up: EVAR, 32.6% [95%CI, 26.9%-38.4%]; OSR, 14.1% [95% CI, 4.0%-30.4%]; stratified log-rank P = 1.06 × 10−7) (Figure 2).No statistically significant differences in long-term reintervention (at maximum follow-up: EVAR,51.8% [95% CI, 48.8%-54.7%]; OSR, 49.6% [95% CI, 42.5%-56.3%]; stratified Gray test P = .68)(Figure 3) or secondary rupture (at maximum follow-up: EVAR, 1.5% [95% CI, 0.9%-2.5%]; OSR,0.8% [95% CI, 0.6%-1.2%]; stratified Gray test, P = .69) were noted (Figure 4).

Sensitivity AnalysisThe inverse probability of treatment–weighted cohort was balanced on all covariates. Cox modelsdemonstrated similar findings between the propensity score–matched cohort and inverseprobability of treatment–weighted cohort (eTable 4 in the Supplement). Endovascular aortic repairwas associated with lower risk of all-cause mortality within 45 days of the procedure (HR, 0.29; 95%CI, 0.22-0.40; P < .001). However, between 1 to 4 years’ follow-up, EVAR was associated with higherall-cause mortality (HR, 1.16; 95% CI, 1.02-1.32; P = .02). Similarly, EVAR was associated with a lowerrisk of MACE within 45 days of the procedure (HR, 0.32; 95% CI, 0.27-0.39; P < .001) but no

Table. Baseline Characteristics of Unmatched and Propensity Score–Matched Cohorts (continued)

Variable

Unmatched Cohort Matched Cohort

No. (%)StandardizedDifference

No. (%)StandardizedDifferenceEVAR (n = 6100) OSR (n = 11 583) EVAR (n = 4010) OSR (n = 4010)

Procedure and Institution Characteristics

Hospital type

Teaching 4966 (81.4) 6442 (55.6) 0.58 3008 (75.0) 2993 (74.6) 0.01

High volume 5563 (91.2) 10 205 (88.1) 0.10 3 626 (90.4) 3 615 (90.1) 0.01

Year of procedure

2003 18 (0.3) 954 (8.2) 0.40 18 (0.4) 15 (0.4) 0.01

2004 12 (0.2) 1321 (11.4) 0.49 12 (0.3) 10 (0.2) 0.01

2005 13 (0.2) 1374 (11.9) 0.50 13 (0.3) 9 (0.2) 0.02

2006 147 (2.4) 1114 (9.6) 0.31 144 (3.6) 143 (3.6) 0

2007 289 (4.7) 996 (8.6) 0.16 269 (6.7) 275 (6.9) 0.01

2008 409 (6.7) 878 (7.6) 0.03 345 (8.6) 352 (8.8) 0.01

2009 538 (8.8) 847 (7.3) 0.06 425 (10.6) 413 (10.3) 0.01

2010 575 (9.4) 756 (6.5) 0.11 410 (10.2) 408 (10.2) 0

2011 714 (11.7) 758 (6.5) 0.18 469 (11.7) 492 (12.3) 0.02

2012 784 (12.9) 635 (5.5) 0.26 444 (11.1) 469 (11.7) 0.02

2013 779 (12.8) 589 (5.1) 0.27 435 (10.8) 424 (10.6) 0.01

2014 777 (12.7) 639 (5.5) 0.25 471 (11.7) 452 (11.3) 0.01

2015 805 (13.2) 580 (5.0) 0.29 440 (11.0) 428 (10.7) 0.01

2016 240 (3.9) 142 (1.2) 0.17 115 (2.9) 120 (3.0) 0.01

Tracer variables

Cataract surgery 1196 (19.6) 1796 (15.5) 0.11 690 (17.2) 740 (18.5) 0.03

Malignancy 1152 (18.9) 1548 (13.4) 0.15 665 (16.6) 597 (14.9) 0.05

Abbreviations: EVAR, endovascular aortic repair; OSR, open surgical repair.a Cell value is represented as a range to eliminate patient reidentification risk, according

to mandatory Institute for Clinical Evaluative Sciences practice.







subsequent differences outside of the perioperative period. The risk of reintervention within 30 daysof repair was significantly lower among patients who underwent EVAR (HR, 0.74; 95% CI, 0.66-0.83;P < .001) but significantly higher from 30 days to 6 months (HR, 1.36; 95% CI, 1.12-1.65; P = .002)and after 2 years (HR, 1.11; 95% CI, 1.01-1.22; P = .03) (eTable 3 in the Supplement). There were nostatistically significant differences in secondary rupture among the matched or sensitivity cohorts.

Discussion

This population-based, retrospective cohort study involving 4010 pairs of propensity score–matchedpatients who underwent EVAR or OSR observed for longer than 13 years demonstrated nostatistically significant differences in long-term survival, reintervention, or secondary rupturebetween patients who underwent EVAR vs those who underwent OSR. In contrast, EVAR wasassociated with higher MACE-free survival throughout follow-up.

The results of this study complement the limited existing long-term data comparing EVAR withOSR for elective AAA repair. To our knowledge, the longest reported follow-up of patients whounderwent EVAR compared with those who underwent OSR to date comes from the EVAR-1multicenter RCT17 of 1252 patients observed for a mean (SD) of 12.7 (1.5) years. That trial

Figure 1. Kaplan-Meier Curve of Survival After Elective Abdominal Aortic Aneurysm (AAA) Treatmentby Endovascular Aortic Repair (EVAR) and Open Surgical Repair (OSR)

0

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Surv

ival

, %

Time Since AAA Repair, y

60

40

20

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36473769

OSREVAR

EVAROSR

Stratified log-rank P = .004. Bonferroni-correctedsignificance at P < 1.25 × 10−5. Shading indicates 95%confidence bands.a Number at risk value or difference between adjacent

values is less than 6. Value is represented as a rangeto eliminate patient reidentification risk, according tomandatory Institute for Clinical Evaluative Sciencespractice.

Figure 2. Kaplan-Meier Curve of Major Adverse Cardiovascular Event (MACE)–Free Survival After ElectiveAbdominal Aortic Aneurysm (AAA) Treatment by Endovascular Aortic Repair (EVAR)and Open Surgical Repair (OSR)

0

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Stratified log-rank P = 1.06 × 10−7. Bonferroni-corrected significance set at P < 1.25 × 10−5. Shadingindicates 95% confidence bands.a Number at risk value or difference between adjacent

values is less than 6. Value is represented as a rangeto eliminate patient re-identification risk, accordingto mandatory Institute for Clinical EvaluativeSciences practice.





demonstrated superior all-cause mortality among patients who underwent EVAR for up to 6 monthsfollowing repair, but this mortality benefit was lost after 6 months, and patients who underwentEVAR demonstrated a higher hazard for all-cause mortality after 8 years (adjusted HR [aHR], 1.25;95% CI, 1.00-1.56; P = .048).17 Similarly, the 9-year results of the Standard Open Surgery VersusEndovascular Repair of AAA (OVER) RCT16 showed loss of the EVAR mortality benefit by 3 years (HR,0.72; 95% CI, 0.51-1.00; P = .05). Additionally, in the longest and largest population-based follow-upof patients who underwent EVAR or OSR, to our knowledge, Schermerhorn et al32 demonstratedlower short-term mortality for patients who underwent EVAR within 30 days (aHR, 0.32; 95% CI,0.29-0.35; P < .001) and from 30 to 90 days of repair (aHR, 0.64; 95% CI, 0.58-0.71; P < .001), withworse outcomes at up to 4 years (aHR, 1.17; 95% CI, 1.13-1.21; P < .001) and after 4 years (aHR, 1.05;95% CI; 1.00-1.09; P = .03). These latter results were most congruent with the findings of our study.

With the accumulation of long-term data, it is becoming clearer that the superiority of EVARmay be limited to the short term. One prevalent explanation for this finding is the high reinterventionrate associated with EVAR. The EVAR-1 trial17 reported a 15-year reintervention rate of 26% in theEVAR group and an aHR of 6.29 (95% CI, 3.09-12.78; P < .001) for any reintervention between 6months and 4 years after EVAR, while the DREAM trial14 reported a reintervention rate ofapproximately 30% at 6 years follow-up, and the OVER trial16 reported a reintervention rate ofapproximately 20% at 9 years follow-up. However, the seminal EVAR vs OSR RCTs used considerable

Figure 3. Cumulative Incidence Function Curve for Reintervention Following Elective Abdominal AorticAneurysm (AAA) Treatment by Endovascular Aortic Repair (EVAR) and Open Surgical Repair (OSR)

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Figure 4. Cumulative Incidence Function Curve for Secondary Rupture Following Elective Abdominal AorticAneurysm (AAA) Treatment by Endovascular Aortic Repair (EVAR) and Open Surgical Repair (OSR)

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values is less than 6. Value is represented as a rangeto eliminate patient reidentification risk, according tomandatory Institute for Clinical Evaluative Sciencespractice.




numbers of now obsolete grafts (approximately 50%). It follows, then, that contemporary, well-adjusted population-based studies of newer grafts with accumulated technical experience shoulddemonstrate a prolongation of the EVAR mortality benefit and a reduction of reintervention rates.This was not the case in our study, as reintervention rates mirrored those demonstrated by theDREAM trial,14 with other population-based studies demonstrating similar results.32-35 Althoughmany reinterventions associated with EVAR have been shown to be minor, a 2018 systematic reviewand meta-analysis36 demonstrated perioperative complication rates of 3.8% and AAA-associatedmortality of 1.8% associated with the treatment of type II endoleak alone. Considering thatapproximately 50% of type II endoleaks have been reported to resolve spontaneously,overtreatment may be increasing EVAR mortality.37,38 Unfortunately, large, contemporary,population-based studies, including our study, do not offer direct insight into whether changes ingraft design have reduced reintervention and mortality. In this study, the assumption that modernendografts were being used for EVAR is not unreasonable, given that the commencement of EVARfunding in Ontario coincides with Health Canada approval of the first endograft and that all approvedendografts in Canada are considered modern. However, no information on specific endograft makesand models is available in Ontario administrative data to verify these assumptions.

Another related explanation for the persistent loss of EVAR mortality benefit may be the moreliberal use of EVAR against manufacturer instructions for use (IFU). Studies have found that despiterelatively stable AAA repair rates, the use of EVAR has increased.6,39-41 Furthermore, a 2018 study42

showed that these rates have increased in populations known to have more challenging anatomy,including women and elderly patients. A 2018 study by Herman et al43 of EVARs from 2005 to 2014demonstrated IFU violations in 43.8% of patients undergoing elective EVAR and that non-IFU EVARswere associated with higher risk of graft-related adverse events (HR, 1.8; 95% CI, 1.05-3.10).Furthermore, a 2017 international study44 of elective AAA repair outcomes during 9 years confirmedworse EVAR perioperative mortality in octogenarians (1.8% vs 0.7%; P < .001) and women (1.9% vs0.9%; P < .001) during the course of the study, suggesting that the long-term benefits of EVAR maybe undermined by too-forceful application. Unfortunately, Ontario administrative data do not allowassessment of adherence to IFU or difficult anatomy, as anatomical characteristics are not availablewithin these data sets.

Additionally, contemporary studies of EVAR compared with OSR may not be demonstratingimprovement in EVAR outcomes owing to concomitant improvements in OSR outcomes throughtime. The initial differences in perioperative mortality may be decreasing with the development ofmultidisciplinary care settings, including experienced cardiovascular intensive care units, thatoptimize OSR outcomes. This study, including data from all centers performing EVAR and OSR inOntario, Canada, whether tertiary, academic, or otherwise, demonstrated 30-day survival for OSRcomparable with the experienced centers involved in the seminal RCTs, largely well-resourcedtertiary care centers with well-developed AAA care programs. In 2015, Schermerhorn et al32

demonstrated earlier merging of OSR and EVAR survival curves when they compared mortality priorto 2005 with mortality after 2005. These findings suggest that OSR outcomes may also beimproving, thus masking improvements in EVAR outcomes.

Endovascular repair has demonstrated a persistent loss of long-term mortality benefit and highreintervention rates in both RCTs and population-based studies. Consequently, economic analyseshave demonstrated EVAR to be cost ineffective, which has led the National Institute for Health andCare Excellence45 in the United Kingdom to recommend against EVAR in its draft of AAAmanagement guidelines. However, the best evidence used to define these guidelines is limited to theseminal RCTs, which are themselves limited by older endografts and early knowledge regardingcomplications and management. Furthermore, EVAR offers potential benefits other than reducedmortality, despite higher reintervention rates. Many studies have uniformly demonstrated lowerperioperative cardiopulmonary complications, shorter lengths of stay in hospitals, and higher ratesof discharge home, among others.2-4 Furthermore, mortality does not reflect the considerableimpact of myocardial infarction and stroke on quality of life among survivors of myocardial infarctions




and strokes.46-48 Consequently, a case can be made for extension of EVAR to younger, healthierpatients with longer life expectancy as opposed to reserving it for the most comorbid patientpopulations or not using it at all. However, the safety of this approach will require even longerfollow-up for patients who undergo EVAR than is currently available, to our knowledge. These datawill ascertain whether any long-term sequelae, such as cancer, exist secondary to EVAR surveillanceand permit greater understanding of the appropriate decision-making approach regarding endoleakand complication management in the context of evolved endograft architecture.

LimitationsThe findings of this study should be interpreted considering several limitations. First, the use ofdiagnostic, procedure, and billings codes to identify patients, covariates, and outcomes is necessarywith the use of administrative data. These codes are subject to coding error and can lack granularity.To mitigate these concerns, validated codes were used for the identification of patients and variableswhere possible, and surrogate markers were used for important covariates that were not coded. Forexample, chronic obstructive pulmonary disease was used as a marker of significant smoking history.Still, information regarding anatomical and technical detail, graft types, adherence to IFU, andindications for procedures, imaging, and clinical follow-up does not exist within Ontarioadministrative data. Next, the use of Ontario administrative data may limit the generalizability of ourfindings to jurisdictions with similar single-payer health care systems. However, our findings weresimilar to those of the major RCTs, in which payment model should not influence outcomes.Additionally, although they are firmly established for the conduct of observational studies,propensity score methods only guarantee balance of treatment groups on the measuredconfounders and do not guarantee absence of residual confounding. However, the congruity of ourfindings with those of long-term RCTs suggests well-specified propensity score models and findingslikely to be free of residual confounding.

Conclusions

This study found no statistically significant difference between outcomes after EVAR and OSR torepair AAA in long-term mortality during more than 13 years of follow-up. Similarly, there were nolong-term differences in reintervention or secondary rupture between the AAA repair approaches.However, EVAR was associated with a higher long-term MACE-free survival rate. The long-termoutcomes after EVAR do not appear to have improved more than OSR since the conduct of theseminal RCTs. The reasons for these findings will require further study, including consideration ofspecific graft makes and models, adherence to IFU, and types and reasons for reintervention.

ARTICLE INFORMATIONAccepted for Publication: May 15, 2019.

Published: July 10, 2019. doi:10.1001/jamanetworkopen.2019.6578

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2019 Salata K et al.JAMA Network Open.

Corresponding Author: Mohammed Al-Omran, MD, MSc, Division of Vascular Surgery, Li Ka Shing KnowledgeInstitute, St Michael’s Hospital, 30 Bond St, Ste 7-074, Bond Wing, Toronto, ON M5B 1W8, Canada([email protected]).

Author Affiliations: Division of Vascular Surgery, University of Toronto, Toronto, Ontario, Canada (Salata, Hussain,de Mestral, Greco, Aljabri, Forbes, Verma, Al-Omran); Division of Vascular Surgery, Li Ka Shing Knowledge Institute,St Michael’s Hospital, Toronto, Ontario, Canada (Salata, Hussain, de Mestral, Greco, Aljabri, Al-Omran);Department of Surgery, King Saud University, Riyadh, Kingdom of Saudi Arabia (Aljabri, Al-Omran); Li Ka ShingCentre for Healthcare Analytics Research and Training (CHART), Li Ka Shing Knowledge Institute, St Michael’sHospital, Toronto, Ontario, Canada (Mamdani); Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto,Ontario, Canada (Mamdani); Division of Vascular Surgery, Peter Munk Cardiac Centre, University Health Network,





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mailto:[email protected]

Toronto, Ontario, Canada (Forbes); Brigham and Women’s Hospital Heart and Vascular Center, Boston,Massachusetts (Bhatt); Harvard Medical School, Boston, Massachusetts (Bhatt); Division of Cardiac Surgery, Li KaShing Knowledge Institute, St Michael’s Hospital, Toronto, Ontario, Canada (Verma); Division of Vascular Surgery,University of Toronto, Toronto, Ontario, Canada (Verma).

Author Contributions: Dr Salata had full access to all of the data in the study and takes responsibility for theintegrity of the data and the accuracy of the data analysis.

Concept and design: Salata, Hussain, Greco, Aljabri, Mamdani, Verma, Al-Omran.

Acquisition, analysis, or interpretation of data: Salata, Hussain, de Mestral, Mamdani, Forbes, Bhatt, Al-Omran.

Drafting of the manuscript: Salata, Verma.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Salata, de Mestral, Mamdani.

Obtained funding: Salata.

Administrative, technical, or material support: Hussain, Aljabri, Mamdani, Al-Omran.

Supervision: de Mestral, Greco, Forbes, Verma, Al-Omran.

Conflict of Interest Disclosures: Dr Salata reported grants from the Canadian Institutes for Health ResearchCanada Graduate Scholarship (Master’s), Frank Goerc and Toronto Academic Vascular Specialists Scholarship,Ontario Graduate Scholarship, and James and Mari Rutka Surgeon Scientist Training Program Scholarship duringthe conduct of the study and grants from Physician Services Incorporated Foundation outside the submitted work.Dr Bhatt reported serving on the advisory boards of Cardax, Elsevier PracticeUpdate Cardiology, MedscapeCardiology, and Regado Biosciences; serving on the boards of directors of the Boston Department of VeteransAffairs (VA) Research Institute, Society of Cardiovascular Patient Care, and TobeSoft; serving as chair of theAmerican Heart Association Quality Oversight Committee, National Cardiovascular Data Registry-MI RegistrySteering Committee, VA Clinical Assessment, Reporting, and Tracking Research and Publications Committee;serving on data monitoring committees for the Cleveland Clinic, Duke Clinical Research Institute, Baim Institute forClinical Research (formerly Harvard Clinical Research Institute, PORTICO trial, funded by St Jude Medical, nowAbbott Laboratories), Mayo Clinic, Icahn School of Medicine at Mount Sinai (for the ENVISAGE trial, funded byDaiichi Sankyo), and Population Health Research Institute; receiving honoraria from the American College ofCardiology (senior associate editor, Clinical Trials and News, ACC.org; vice-chair, ACC Accreditation Committee),Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steeringcommittee funded by Boehringer Ingelheim), Belvoir Publications (editor in chief, Harvard Heart Letter), DukeClinical Research Institute (clinical trial steering committees), HMP Global (editor in chief, Journal of InvasiveCardiology), Journal of the American College of Cardiology (guest editor and associate editor), Population HealthResearch Institute (for the COMPASS operations committee, publications committee, steering committee, and USnational coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today’s Intervention),Society of Cardiovascular Patient Care (secretary and treasurer), and WebMD (continuing medical educationsteering committees); serving as deputy editor for Clinical Cardiology; receiving research funding from AbbottLaboratories, Amarin Corporation, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, ChiesiFarmaceutici, Eisai, Ethicon Inc, Forest Laboratories, Idorsia, Ironwood Pharmaceuticals, Ischemix, Eli Lilly andCompany, Medtronic, Pfizer, PhaseBio Pharmaceuticals, Regeneron, Roche Holding, Sanofi, SynapticPharmaceuticals, and The Medicines Company; receiving royalties from Elsevier (editor, CardiovascularIntervention: A Companion to Braunwald’s Heart Disease); serving as site coinvestigator at Biotronik, BostonScientific, St Jude Medical (now Abbott Laboratories), and Svelte; serving as trustee for the American College ofCardiology; and conducting unfunded research for FlowCo Solutions, Merck and Co, Novo Nordisk, PLx Pharma,and Takeda Pharmaceutical. Dr Verma reported grants and personal fees from Amgen and Boehringher Ingelheim;personal fees from AstraZeneca, Bayer, Eli Lilly and Company, Janssen, Merck and Co, Novartis, Novo Nordisk,Sanofi, Servier, and Valeant; and grants from Bristol-Myers Squibb outside the submitted work. No otherdisclosures were reported.

Funding/Support: This study was supported by the Institute for Clinical Evaluative Sciences (ICES), which isfunded by an annual grant from the Ontario Ministry of Health and Long-Term Care (MOHLTC). This work wasjointly funded by the Division of Vascular Surgery at St Michael’s Hospital, Toronto, Ontario, Canada, and fundsfrom the Department of Surgery, King Saud University, Riyadh, Kingdom of Saudi Arabia. Dr Salata is supported inpart by the Canadian Institutes of Health Research Canada Graduate Scholarship Master’s salary support award,the Goerc and Toronto Academic Vascular Specialists Surgeon Scientist Training Program Scholarship, and theOntario Graduate Scholarship.

Role of the Funder/Sponsor: The funders had no role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; anddecision to submit the manuscript for publication.




Disclaimer: The opinions, results, and conclusions reported in this article are those of the authors and areindependent from the funding sources. No endorsement by ICES or the Ontario MOHLTC was intended or shouldbe inferred. Parts of this material are based on data or information compiled and provided by the CanadianInstitute of Health Information. However, the analyses, conclusions, opinions, and statements expressed in thematerial are those of the authors and not necessarily those of the Canadian Institute of Health Information.

Additional Contributions: Atul Sivaswamy, MSc (ICES, Toronto, Ontario, Canada), helped with data set creationand analysis. No direct compensation was provided. However, administrative and analyst fees were paid to ICESfor provision of the above services.

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SUPPLEMENT.eTable 1. Summary of Institute for Clinical Evaluative Sciences Databases UsedeTable 2. Covariate and Outcome Definitions and CodeseTable 3. Survival and Cumulative Incidence Rates in Unmatched and Matched CohortseTable 4. Hazard Ratios From Cox Proportional Hazards Models for Matched and Inverse Probability of Treatment–Weighted CohortseReferences.













https://www.nice.org.uk/guidance/GID-CGWAVE0769/documents/short-version-of-draft-guideline

https://dx.doi.org/10.1186/s12955-017-0730-9

https://dx.doi.org/10.1186/s12955-017-0730-9

https://dx.doi.org/10.1007/s10072-017-3172-6

https://dx.doi.org/10.1186/s12872-017-0687-y

comparison of outcomes in elective endovascular aortic

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