Aortic Aneurysm, Abdominal Clinical Trial
Official title:
Expertise Based Randomized Controlled Trial of Open Versus Endovascular Repair of Abdominal Aortic Aneurysms: A Pilot Study
Objectives.
To study the feasibility of an expertise-based randomized controlled trial (RCT) testing the
role of traditional surgery (OPEN) versus endovascular repair (EVAR) for abdominal aortic
aneurysms (AAA).
Study design.
We will conduct an expertise-based RCT comparing OPEN to EVAR of non-urgent abdominal aortic
aneurysms in patients referred to vascular surgeons practicing at Hamilton Health Sciences,
to determine the rate of death and other complications. Quality of life and status at 6
months will also be recorded. The ultimate goal is to determine the feasibility of
conducting a pragmatic expertise-based RCT and to inform a future larger study at a national
level.
Background. The prevalence in individuals over 65 years of age is 6% (95% Confidence
Interval [CI] 5 - 6)(1-4)in men and 1% (95% CI 1 – 2) in women.(5) AAA confers a risk of
spontaneous rupture and death: the in-hospital mortality rate of ruptured aneurysms in
Ontario was estimated at 40.8%.(6) Prevention of spontaneous rupture is the rationale for
surgical intervention. Evidence has established that elective open surgery for AAAs > 5.5cm
increases survival(7), but the 30-day perioperative mortality for elective open repair of
AAA can be as high as 8%.(8-17) Phase I and II trials have found that endovascular repair is
a ‘viable and effective treatment’ for AAA disease (18;19); the theoretical benefits include
avoidance of laparotomy and no aortic clamping.
The results of RCTs (DREAM and EVAR-1)(20;21) have left unanswered the indications for
endovascular repair compared with open surgery because of problems with definition of
outcomes, lack of statistical power, and surgical expertise (surgeons needed to have done at
least 20 surgeries with or without supervision). The only studies addressing the issue of
expertise in this field suggests that 60 EVAR need to be done to achieve less than 10%
complications (22), and a time interval of less than 10 days between procedures is important
to maintain competence and reduce complications.(23) In addition the two RCTs used a
conventional design and we have reported that this has intrinsic pitfalls. We argued that in
surgery, particularly when a new technique is studied, another approach should be used: the
expertise based RCT.(24) Conventional RCTs typically randomize participants to one of two
interventions (A or B) and the same clinician give intervention A to some participants and B
to others. The expertise based randomized controlled trial, randomizes participants to
clinicians with expertise in intervention A or clinicians with expertise in intervention B,
and the clinicians perform only the procedure for which they have expertise.
Study Design/Participants
We will conduct an expertise based RCT comparing open repair with EVAR repair of elective
infrarenal AAAs. This is a pilot to determine the feasibility of a large pragmatic expertise
based RCT of open versus EVAR repair.
We will consider all patients with an AAA determined to require non-urgent repair after
assessment by one of the participating surgeons. The second inclusion criterion is that the
blinded measurement team must deem a patient to fulfill the anatomic eligibility criteria.
Location of Investigation
This pilot study will be conducted at a single institution: Hamilton Health Sciences,
Hamilton General Hospital. This centre will serve as the coordinating site for the future
multicentre randomized controlled trial, and based on the high volume practices of the
surgeons at the Hamilton General Hospital, will likely provide the largest pool of eligible
patients. Protocols and standard operating procedures for a single site will be developed
for this pilot, which will become standards for the larger trial. The decision to use a
single centre for this pilot study is based in the high expected surgical volume that makes
our recruitment rate realistic, in addition to the cost savings of conducting a trial close
to investigators and surrounded by known infrastructure.
Patient Recruitment
Once a patient is deemed eligible, the study nurse will provide the patient with details of
the study protocol and explanation of goals of the investigation, and obtain informed
consent.
Randomization and Allocation
The study nurse will be contacted by the surgeons’ offices to screen all patients referred
to participating vascular surgeons on the first visit to the office and submit a
standardized electronic form accessible on a secure, encrypted website. This will document
baseline demographics for referred patients including key eligibility criteria. If these are
met, the study nurse will contact the patient, explain the study, determine the remaining
eligibility criteria and obtain consent. The nurse will use the electronic database to
randomly allocate the patient to open or endovascular repair. We will ensure concealment of
allocation through the use of a randomization and allocation process housed on an encrypted
website monitored by a data coordinator external to the study protocol. This process has
been successfully developed within the St Joseph's Nephrology, Thromboembolism and Vascular
research group. Randomization using random-sized permuted block technique will ensure
balanced distribution of patients and concealment of allocation. Once allocation has
occurred, the study nurse will coordinate patient appointments to the appropriate surgeon.
Patients who do not meet eligibility requirements will return to their original surgeon for
disclosure of results and treatment.
Patient Follow-up
The study nurse will meet the patient, document baseline characteristics and perform blood
work at the preoperative clinic visit. The study nurse will see patients daily after
surgery, arrange daily blood work and document all outcome events using standardized case
report forms until discharged from hospital. An outcome assessor committee independent of
the study and blinded to treatment allocation will adjudicate all outcome events. The study
nurse will see all patients at 3-month intervals for 6 months. The use of a 6-month outcome
threshold is for purposes of assessing feasibility in this pilot study only. The larger
multicentre trial will plan to evaluate outcomes up to five years, addressing the long term
concerns that have been raised in RCTs.
Evaluation of Pilot Objectives
We will consider the pilot study a success if we can:
1. Recruit 30 patients in 40 weeks
2. Obtain a complete follow-up on 95% of the trial patients
3. Demonstrate the feasibility of using a web-based system to randomize and follow
patients in this trial, and for outcome adjudication, and
4. Document the resources (e.g., personnel time) required to conduct this trial.
Ethical Considerations
All patients in this study will provide informed consent prior to participation, and the
protocol will be reviewed by the Ethics Review Board of Hamilton Health Sciences.
Reference List
1. Lindholt JS, Juul S, Fasting H, Henneberg EW. Screening for abdominal aortic aneurysms:
single centre randomised controlled trial. BMJ, 330: 750.
2. Ashton HA, Buxton MJ, Day NE et al. The Multicentre Aneurysm Screening Study (MASS)
into the effect of abdominal aortic aneurysm screening on mortality in men: a
randomised controlled trial. Lancet, 360: 1531-1539.
3. Norman PE, Jamrozik K, Lawrence-Brown MM et al. Population based randomised controlled
trial on impact of screening on mortality from abdominal aortic aneurysm. BMJ, 329:
1259.
4. Scott RA, Vardulaki KA, Walker NM, Day NE, Duffy SW, Ashton HA. The long-term benefits
of a single scan for abdominal aortic aneurysm (AAA) at age 65. European Journal of
Vascular & Endovascular Surgery, 21: 535-540.
5. Scott RA, Bridgewater SG, Ashton HA. Randomized clinical trial of screening for
abdominal aortic aneurysm in women. Br.J.Surg., 89: 283-285.
6. Dueck AD, Kucey DS, Johnston KW, Alter D, Laupacis A. Survival after ruptured abdominal
aortic aneurysm: effect of patient, surgeon, and hospital factors. J.Vasc.Surg., 39:
1253-1260.
7. Mortality results for randomised controlled trial of early elective surgery or
ultrasonographic surveillance for small abdominal aortic aneurysms. The UK Small
Aneurysm Trial Participants. Lancet, 352: 1649-1655.
8. Ernst CB. Abdominal aortic aneurysm. N.Engl.J.Med., 328: 1167-1172.
9. Zarins CK, Harris EJ, Jr. Operative repair for aortic aneurysms: the gold standard.
J.Endovasc.Surg., 4: 232-241.
10. Lawrence PF, Gazak C, Bhirangi L et al. The epidemiology of surgically repaired
aneurysms in the United States. J.Vasc.Surg., 30: 632-640.
11. Heller JA, Weinberg A, Arons R et al. Two decades of abdominal aortic aneurysm repair:
have we made any progress? J.Vasc.Surg., 32: 1091-1100.
12. Galland RB. Mortality following elective infrarenal aortic reconstruction: a Joint
Vascular Research Group study. Br.J.Surg., 85: 633-636.
13. Johnston KW, Scobie TK. Multicenter prospective study of nonruptured abdominal aortic
aneurysms. I. Population and operative management. J.Vasc.Surg., 7: 69-81.
14. Bradbury AW, Adam DJ, Makhdoomi KR et al. A 21-year experience of abdominal aortic
aneurysm operations in Edinburgh. Br.J.Surg., 85: 645-647.
15. Bayly PJ, Matthews JN, Dobson PM, Price ML, Thomas DG. In-hospital mortality from
abdominal aortic surgery in Great Britain and Ireland: Vascular Anaesthesia Society
audit. Br.J.Surg., 88: 687-692.
16. Huber TS, Wang JG, Derrow AE et al. Experience in the United States with intact
abdominal aortic aneurysm repair. J.Vasc.Surg., 33: 304-310.
17. Kazmers A, Jacobs L, Perkins A, Lindenauer SM, Bates E. Abdominal aortic aneurysm
repair in Veterans Affairs medical centers. J.Vasc.Surg., 23: 191-200.
18. Thomas SM, Gaines PA, Beard JD. Short-term (30-day) outcome of endovascular treatment
of abdominal aortic aneurism: results from the prospective Registry of Endovascular
Treatment of Abdominal Aortic Aneurism (RETA). Eur.J.Vasc.Endovasc.Surg., 21: 57-64.
19. 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 Stent-graft Techniques for abdominal aortic Aneurysm Repair.
J.Endovasc.Surg., 4: 72-77.
20. Prinssen M, Verhoeven EL, Buth J et al. A randomized trial comparing conventional and
endovascular repair of abdominal aortic aneurysms. N.Engl.J.Med., 351: 1607-1618.
21. 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, 364:
843-848.
22. Forbes TL, DeRose G, Kribs SW, Harris KA. Cumulative sum failure analysis of the
learning curve with endovascular abdominal aortic aneurysm repair. J.Vasc.Surg., 39:
102-108.
23. Lobato AC, Rodriguez-Lopez J, Diethrich EB. Learning curve for endovascular abdominal
aortic aneurysm repair: evaluation of a 277-patient single-center experience.
J.Endovasc.Ther., 9: 262-268.
24. Devereaux PJ, Bhandari M, Clarke M et al. Need for expertise based randomised
controlled trials. BMJ, 330: 88.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment
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