AAA Repair: Early Intervention or Wait and See?

By Jeff Evans

LONDON -- Potential flaws in the Endovascular Aneurysm Repair 2 (EVAR 2) trial are making it difficult for experts to agree on whether to perform early endovascular repair of abdominal aortic aneurysms in patients at high risk for open repair, or to wait for patients' fitness to improve before the repair is made.

Speakers at the Charing Cross 28th International Symposium were at odds in determining whether the definition of high-risk patients, treatment delay, or surgeon inexperience may have biased the results of the EVAR 2 trial away from endovascular intervention and toward watchful waiting and improving patients' fitness.

Wait to Intervene on Smaller AAAs?

Studies on early endovascular repair have shown that only those patients with an abdominal aortic aneurysm (AAA) with a diameter greater than 7 cm have a rupture risk greater than 10%, said Dr. Janet T. Powell of the Imperial College London in the session designed to debate the EVAR 2 midterm results.

"For all patients with an aneurysm diameter less than 7 cm--and you can see this is the majority of patients in the EVAR 2 trial--the risk of rupture is likely to be less than the risk of an early EVAR," she said, highlighting the case against early repair.

In the EVAR 2 trial, 338 AAA patients who were deemed unfit for open surgery were randomized to receive endovascular stenting or no intervention. The range of AAA diameters in the trial was 6.0-7.4 cm, with a median of about 6.4 cm.

Improving Fitness or Hoping Against Rupture?

Of the 172 patients in the no-intervention arm of the trial, 47 crossed over to the intervention arm (35 endovascular and 12 open repairs). Although the reasons for why the crossover rate was so high were "poorly described" in the study, Dr. Powell said that the patients' case data give a "strong suspicion" that their fitness was being improved in many instances.

The frailty of patients in the EVAR 2 trial means that measures to improve their fitness so that they can survive an intervention--such as taking statins and exercising--will need to be undertaken over a course of at least 3 months, she said.

But Dr. Kim J. Hodgson called these measures to improve fitness unrealistic in the real world, given the risk of aneurysm rupture. ?-Blockers and statins administered before surgery have been shown to improve outcomes, but the time frame for when to use them has not been studied, he said.

Rather than becoming fitter, those 47 patients probably had growing aneurysms and they became increasingly unhappy with waiting, said Dr. Hodgson, who is the chair of the division of vascular surgery at Southern Illinois University, Springfield.

The EVAR 2 trial is "presumed to be an authoritative study because it was randomized and controlled," said Dr. Hodgson; its data were analyzed "on an intention-to-treat basis, but in my opinion the study was actually conducted on a pragmatic basis as an intention-to-survive trial because patients and physicians crossed over [to the interventional arm] with such great frequency."

High-Risk Criteria Under Scrutiny

The open-ended definition of high-risk patients in the EVAR 2 study may be evidenced by the fact that five high-risk patients who were deemed unable to undergo open repair actually underwent open surgery when their AAAs ruptured; two of the five patients survived beyond 30 days.

"These are outcomes that rival those of repair for all ruptured aneurysms, so in my mind I really have to question the assignment of risk of many of these patients," Dr. Hodgson said.

Suitability for elective open repair was determined locally at each center that participated in the EVAR 2 trial; each center received guidelines for cardiac, respiratory, and renal status to aid decision making.

"High risk" as defined in many centers "is not as high risk as some would have us believe," Dr. Hodgson noted.

The results of studies that were done involving oxygen-dependent patients who received open or endovascular repairs for 6-cm AAAs have showed survival rates of nearly 50% after 42 months (J. Vasc. Surg. 2005;42:650-3).

This finding compares favorably with the 20% survival rate of oxygen-dependent patients who had untreated 6-cm AAAs and who neither died nor experienced a rupture after 34 months (Acta Chir. Belg. 2001;101:11-6).

Dr. Hodgson raised an additional problem with the trial: Surgeons were required to have experience with only 20 previous endovascular repair procedures to participate in EVAR 2, but "many of us would consider that [number] to be well within the learning curve for this relatively complex procedure," he said. Such inexperience with endovascular repair may have resulted in greater numbers of certain complications--such as type I (6%) and type III (3%) endoleaks and graft limb thrombosis (4%)--than would normally be expected.

Three patients waited more than 1 year because they had what was called "problematic aortic anatomy," which may have meant that these patients should never have been included in the interventional arm of EVAR 2. "People were pushing this technology to try and offer it to patients who maybe really didn't qualify for it," Dr. Hodgson said.

In defense of early repair, despite the EVAR 2 results, Dr. Rodney A. White, director of vascular surgery at the Harbor-UCLA Medical Center, Torrance, Calif., said that "we're going to agree from the beginning that big aneurysms are a problem," and that patients with a high enough risk for rupture will need to be treated regardless of whether they are fit or not."

But, he pointed out, both treatment delay and differences in the criteria that were used to define patients who are unfit for surgery may explain the difference in the 30-day mortality of 150 patients who received endovascular repair in the EVAR 2 trial (9%) and 2,908 patients in the Lifeline Registry for Aneurysm Repair who also received endovascular repair (2%), Dr. White said.

He reported on 2,908 patients in the Lifeline registry who had their AAAs endovascularly repaired in investigational device exemption clinical trials.

The Lifeline registry was established by industry and the Food and Drug Administration as a mechanism for reporting and conducting surveillance on commercial devices and those that are used under investigational device exemptions; every patient's record in the registry is reviewed independently.

Both endovascular and open repair in the Lifeline registry had mortality approaching 30% after 4 years of follow-up, compared with 62% mortality in the intervention arm and 66% mortality in the no-intervention arm after 4 years in the EVAR 2 trial.

"There is a total mismatch in the data. It's either in the auditing [or] in the follow-up, or somehow their definitions don't make any sense and we're maybe not characterizing the patients the same," he said.

About 30%-40% of the patients in the Lifeline registry match the risk criteria used to enter patients into the EVAR 2 trial, Dr. White said.

Of the 150 patients who received endovascular repair in the EVAR 2 study, 20 patients died from a ruptured AAA either before or after the operation, but 9 of these patients died of their rupture while waiting for an elective repair.

One could assume, said Dr. White, that these nine patients could have survived if they had been treated without delay. If these nine patients are subtracted from the 13 patients in the intervention arm who died within 30 days of the operation, then the 30-day mortality drops from 9% to 3%.

This is close to the 30-day mortality of 2% that was observed in the Lifeline registry, in which high-risk patients were treated right away and did not have to wait for randomization or any other issue, according to Dr. White.

Patients in the interventional arm of the EVAR 2 trial waited a median of 57 days to receive endovascular repair.

Thus, randomization itself could have been a risk factor for death because of the delay in receiving an intervention, Dr. White suggested.