Treating Smaller AAAs
Does the availability of endovascular grafts change the size threshold for repair?
Open surgical repair of abdominal aortic aneurysms (AAAs) has been the standard of care for more than 50 years. Treatment is directed at decreasing the risk of aneurysm rupture and patient mortality. Initially, however, a relatively high morbidity and mortality rate was unavoidable with the open surgical aneurysm repair. Although the risk of the procedure has diminished considerably since its inception, the perioperative mortality rate remains in the range of 2% to 5%, and as is often the case, published results of carefully executed clinical trials document a somewhat higher mortality rate than single-center series.
As a result of the morbidity and mortality associated with an open approach, aneurysm repair has been discouraged until the aneurysm reaches a considerable size. In fact, a threshold of 6 cm was used to advocate repair several decades ago, at a time when the perioperative mortality rate exceeded present levels. As the results of operations improved, however, this threshold gradually decreased to the point where most clinicians now offer operative repair when the aneurysm diameter exceeds 5 cm to 5.5 cm in diameter. Although an increased risk of rupture has been found in certain subsets of patients (eg, females, patients with diastolic hypertension, and those with chronic pulmonary disease), a raw diameter measurement alone is still used as the sole guide for treatment. Moreover, no clear guidelines have been formulated for modifying this threshold based on any of the aforementioned patient subsets.
Two well-designed, randomized, prospective, multicenter trials evaluated surveillance versus early repair of AAAs. The United Kingdom Small Aneurysm Trial entered 1,090 patients into a protocol of serial ultrasounds versus early open surgical repair. It is interesting to note that the vast majority of patients in the surveillance group eventually underwent open surgical repair for the development of symptoms or enlargement. At 8 years of follow-up, approximately 75% of the patients underwent repair. Probably the most important finding from this study was the observation of a significantly improved mortality rate in the early repair treatment arm, as assessed by Kaplan-Meier analysis. Nevertheless, the trialists ascribed this mortality benefit to lifestyle modifications associated with early surgery—specifically, to a greater frequency of smoking cessation in the early repair group.
The United States Veterans Administration organized a similar study (the ADAM trial). In this study, 1,136 patients were randomized to ultrasound surveillance versus early surgical repair. Although the need for open surgical repair was also high in this study (approximately 70% at 8 years), the findings of this study differed considerably from those of the United Kingdom trial. No apparent survival benefit was detected in the early surgical treatment arm of the ADAM trial. The Kaplan-Meier survival curves for the surveillance and the immediate repair treatment arms are virtually identical. Also, these results were noted in spite of a perioperative mortality rate that was substantially lower than that of the United Kingdom study.
These two multicenter trials present conflicting data on whether smaller aneurysms (4 cm to 5.5 cm in diameter) should be offered early open surgical repair. The results of these studies, however, must be taken in the context of the relatively high mortality rates associated with the open surgical repair of an aneurysm. In the United Kingdom trial, the perioperative mortality rate was 5.4%. In the ADAM trial, the corresponding rate was 2.1%. If a procedure could be performed with a considerably lower perioperative mortality rate than open surgery, such a procedure might demonstrate value in the treatment of smaller AAAs. For instance, taking it to the extreme, what if we had a “pill” that would cure an AAA? Such a pharmaceutical approach would be used in everyone with a AAA, even if the aneurysm were only 2.5 cm or 3 cm in diameter.
Clearly, we do not have a pill to treat AAAs. However, extending this logic to minimally invasive (endovascular) aneurysm repair, if the perioperative mortality rate of minimally invasive aneurysm repair were considerably lower than the rates seen in the United Kingdom and ADAM trials, and if a similar rate of morbidity and mortality were seen in the observational arms of these two studies, one would predict that endovascular repair would “beat” surveillance for smaller AAAs. Such pure speculation, however, must be tested in the context of a well-powered, randomized clinical trial.
CURRENT SMALL ANEURYSM TRIALS
Two such trials have been discussed and are in the planning phase. The first (CAESAR), a study headed by Piergiorgio Cao, MD, of Perugia, Italy, was to be funded by Cook Incorporated (Bloomington, IN) and would utilize the Zenith device to treat aneurysms between 4 cm and 5.5 cm in diameter. The second study (PIVOTAL), organized by myself and funded by Medtronic, Inc. (Santa Rosa, CA), is designed to utilize the recently modified AneuRx device in patients with AAAs between 4 cm and 5 cm in diameter.
Of great importance is the endpoint in a randomized trial of immediate endovascular repair versus ultrasound surveillance. We treat aneurysms to prevent rupture and death; therefore, the most appropriate endpoint may be the occurrence of either rupture or aneurysm-related death, attempting to exclude deaths not attributable to the aneurysm or its repair. The use of an endpoint such as aneurysm-related death obviates the “noise” associated with the use of all-cause mortality at the primary endpoint. Although there are some problems sorting out whether a death was related to the aneurysm versus other causes, the use of an adjudication committee will improve specificity. The loss of diminished “sensitivity” (ie, patients who died of the aneurysm but for whom such a cause of death was not a certainty) only increases the need for a larger sample size, as long as the chance of missing an aneurysm-related death is similar in the two treatment arms.
PIVOTAL Trial Design
The design of the PIVOTAL trial is that patients with an aneurysm documented on CT scan between 4 cm and 5 cm in diameter with anatomy suitable for endovascular repair with the Medtronic AneuRx device will be eligible for inclusion. Sample size calculations suggest that approximately 1,700 patients will need to be enrolled, equally allocated to a test group and a control group. The patients will undergo early endovascular repair with the AneuRx device or observation with serial ultrasound studies performed at 6-month intervals. Patients in the surveillance arm will be treated with an endovascular device or an open surgical procedure, at the discretion of the investigator for the development of symptoms or for aneurysm sac growth. The primary endpoint, rupture or aneurysm-related death, will be assessed at 3 years, but the patients will be followed for a total of 5 years.
If endovascular treatment of small aneurysms in this randomized trial is associated with the morbidity and mortality noted by Zarins in his review of the AneuRx pre-market approval database,1 or noted by myself in the Cleveland Clinic review of over 400 small aneurysms repaired with endografts,2 then there is a good chance that the minimally invasive approach will be associated with diminished morbidity and mortality compared to ultrasound surveillance. In fact, our own experience suggests that smaller aneurysms can be treated with a perioperative mortality rate well below 1%, and a long-term risk of rupture that is exceedingly low.
Whether this hypothesis can be proven with the PIVOTAL study is a question that can only be answered after the enrollment and 3-year follow-up of almost 1,700 subjects. This is an important question, however, and the investigators and the study sponsor should be congratulated for their tenacity in making this trial a reality. We expect enrollment to begin during the second quarter of 2005, with completion of enrollment in 2006, analysis of the primary endpoint in 2009, and study-close in 2011. In the meantime, clinicians must continue to use their best clinical judgment to determine whether an individual patient is best served with early repair or close observation. n
Kenneth Ouriel, MD, is from The Department of Vascular Surgery, The Cleveland Clinic Foundation, Cleveland, Ohio. He has disclosed that he holds no financial interest in any product or manufacturer mentioned herein. Dr. Ouriel may be reached at (216) 445-3464; email@example.com.
1. Zarins CK, Crabtree T, Arko FR, et al. Endovascular repair or surveillance of patients with small AAA. Presented at the European Society of Vascular surgery, 2004.
2. Ouriel K, Srivastava SD, Sarac TP, et al. Disparate outcome after endovascular treatment of small versus large abdominal aortic aneurysm. J Vasc Surg. 2003;37.