The Food and Drug Administration (FDA) approved the marketing of two endovascular prosthetic graft devices for the treatment of infrarenal abdominal aortic aneurysm (AAA) in September 1999. Endovascular vessel grafting is perhaps the most important change in vascular surgical practice to have taken place in the five decades since the introduction of AAA resection. This has also stimulated investigations into a variety of percutaneous and endovascular treatment approaches for vascular pathologic conditions. Since becoming commercially available, approximately 20,000 of these devices have been implanted worldwide and have been the subject of numerous academic reports highlighting both the clinical benefits and concerns for complications associated with an important but as yet evolving technology.1 This editorial provides an FDA perspective on the performance of the device since its approval and how this must influence future use of the endovascular graft.
For approval of the marketing of implanted medical devices that present significant risk to patients in the event of failure, as endovascular grafts do, the FDA requires establishment of both safety and effectiveness when used as labeled. Evidence of this is obtained from a variety of sources that may include in vivo and in vitro experiments and, most important, clinical trials. A clinical study in which a significant risk device is used must be undertaken with protocols approved by the FDA in an application for an investigational device exemption (IDE). The sponsor of a new device submits a premarket approval (PMA) application to the FDA that includes data from the IDE studies. After an in-house review by a multidisciplinary team, the FDA will present the application to a committee of nongovernment experts, in the case of vascular prostheses, the Circulatory System Advisory Panel, for a recommendation about market approval. The Advisory Panel reviews the application in a public forum with opportunity provided for relevant input from any interested parties.2
This procedure was followed to gain approval of PMA applications submitted by Medtronic AVE for their AneuRx device, and by Guidant Corporation for the Ancure system. Clinical trials for these PMA applications began as early as 1994. Inclusion criteria for the pivotal clinical trials limited treatment to nonemergency cases meeting indications for surgical aneurysmectomy. Nonrandomized controls underwent open surgical treatment. In the Ancure study, controls included patients in whom aneurysm anatomy precluded endovascular grafting (eg, inadequate aortic anchoring sites). In the Ancure study 268 patients were enrolled who were receiving bifurcated grafts and 153 who were treated with tube grafts at 22 medical centers. A concurrent control cohort of 111 patients underwent conventional surgery. The AneuRx study was conducted at 13 clinical centers where 66 surgical controls were enrolled as a modified concurrent control group before the recruitment of 416 patients into the pivotal study with a bifurcated endovascular aortic graft only for the experimental arm was initiated. These less robust nonrandomized control study designs were necessary because of the difficulty encountered in recruiting patients to a randomized study once the endovascular option became available. Patients were followed up for at least 1 year for adverse events, clinical utility, and patient acceptance measured with quality of life evaluations. Effectiveness was assessed as procedural success in deployment, success with exclusion of aneurysm from the circulation, and absence of AAA rupture. Change in aneurysm size was also captured. Follow-up of treatment arms included regular imaging reviewed by independent core laboratories. The outcome of these studies is published in “Summaries of Safety and Effectiveness” (SS&E) and is included in the device labeling.3, 4 The clinical data, supported with both in vivo and in vitro experiments, indicated a clinical utility for the device on the basis of reduced morbidity and improved quality of life and acceptable safety and effectiveness variables. A mortality benefit compared with open surgery was not demonstrated despite the lesser invasiveness of this endovascular procedure. Concern for an early disturbing incidence of perigraft flow (endoleak) was assuaged by the elimination of communication of the AAA sac with the circulation in the course of patient follow-up.
The PMA application process provides a snapshot of device performance in a highly controlled clinical environment. The limited 1-year follow-up was considered acceptable for outcomes of a study with patients exhibiting considerable comorbidity. The Advisory Panel, in recommending market approval, addressed the duration of follow-up with a requirement that all study patients continue to be followed up for 5 years. The FDA found in an assessment of risk versus benefit and the related clinical utility that the data supported device approval and concurred with the Advisory Panel recommendation. The FDA did not stipulate criteria for patient selection, which was deemed a practice of medicine issue by the Advisory Panel.5 The FDA does, however, publish the data related to the PMA approval process in the “Summaries of Safety and Effectiveness” and the device labeling, and these are accessible to clinicians for decisions about patient selection and other clinical issues.
The real world practice of vascular surgery differs considerably from that of a clinical study that adheres to a rigid protocol and is undertaken at well-recognized clinical centers. The FDA monitors device performance in this open market environment. In doing so it depends to a large degree on passive reporting in the clinical literature and at professional conferences, annual reports that manufacturers are required to submit on PMA device status to the Agency, and the mandatory medical device reporting by sponsors to the FDA concerning device-related adverse events. The FDA is, however, in the unique position of having recourse to the raw data available from a required postmarket study undertaken with an approved protocol. The FDA can respond to failures in a device's structural integrity and function with regulatory interventions at the manufacturing level ranging from rescission of market approval to requiring mailing of informational “Dear Doctor” letters. On the other hand, the Agency has limited instruments available with which to influence clinical practice. The clinical milieu reacts largely to peer-review influences. The FDA does accept a responsibility to disseminate any information surfacing during marketing that is either a supplement to or a correction of that contained in its published summary of safety and effectiveness and the labeling.
The treatment of AAA with endovascular grafts is in an early phase of both the technologic development and determination of the appropriate arena of clinical applicability. In fact, the FDA has reviewed more than 36 IDE applications for endovascular aortic devices. The two devices approved for marketing are quite dissimilar in their structural characteristics. The Ancure system has active fixation of the graft with hooks and a flexible, unsupported graft prosthesis. The AneuRx has the graft supported by stents in its entire length and relies on radial force applied to the aortic wall by self-expanding stents for fixation. The AneuRx device has a modular construction where one iliac limb is separately introduced into the aortic trunk to create the bifurcated aortoiliac configuration. The Ancure system is preconstructed as either a bifurcated or tubular device. Both devices underwent design changes in the course of the IDE study. In many instances, improvements were made to address procedural failure. Bailout surgical repair of injury occurring during endovascular procedure or abandonment with conversion to open aneurysmectomy has been recently reported as necessary in 2% to 7% of cases.6, 7
The importance of accurately establishing the anatomy and the degenerative pathology of the AAA and related aorta and iliac arteries to ensure procedural success, stable anchoring of the graft, and satisfactory long-term outcome is critical. The conventional imaging of aneurysmal disease, which relies on ultrasound and aortography, is generally inadequate for the endovascular procedure. Contrast-enhanced computerized tomography, often supplemented with three-dimensional reconstruction, is increasingly viewed as necessary for appropriate patient preoperative selection and postprocedural follow-up.8
Continuing experience has confirmed that the anticipated significant improvement in perioperative morbidity is achieved with the reduction of hospital stay to 4 or 5 days after endovascular-treated AAA, compared with an average hospitalization of 10 days after surgical aneurysmectomy.8 The perioperative mortality rate for the endovascular procedure has been reported comparable to that for open surgery. The mortality rate in one study was found to be 1.5% for patients in ASA Class 1 and 12% for those in Class 4, conceptually those most likely to have benefited from this less-invasive procedure.6
The primary objective in treating AAA is to obviate risk of catastrophic rupture. This is almost invariably accomplished with open surgical treatment; a 0.44% rate of false aneurysm rupture was reported in a 6-year follow-up of one series.9 Delayed rupture, however, after endovascular treatment has been reported in a registry of 2464 patients with a cumulative rate at 1 year of approximately 1%6 and of 2% in 1046 patients in an IDE study followed for 3 years.10 These figures are probably conservative because only patients positively identified with ruptures are computed, excluding patients with an unidentified cause of death. The mortality rate of emergency conversion surgery for rupture in both reports was similar to that for de novo aneurysm rupture at 40% to 50%.
Imaging may identify signs that presage occurrence of delayed rupture after endovascular treatment of AAA. While some of the premonitory signs have been linked to the pathogenesis of delayed rupture, others remain conjectural. Factors incriminated include persistent perigraft flow, particularly of Type 1; migration of attachment cuffs, possibly associated with ongoing aortic cuff dilatation; loss of integrity of graft prosthesis due to stent fractures, suture breaks, or fabric tears; extreme graft kinking; and separation of modular components, possibly due to aneurysm remodeling. Aneurysm enlargement, with or without endoleak, is an extremely sensitive indicator for risk of impending aneurysm rupture. Failure of an aneurysm to diminish in size and the effect of transmitted systolic pulsatile pressure to the aneurysm wall, termed endopressure, are perceived as more controversial causes for delayed rupture. The risk for delayed rupture is sufficiently substantial to justify the need for moni toring AAA patients treated with endovascular grafts indefinitely for signs of treatment failure. Repetitive contrastenhanced computerized tomography and color flow Doppler interrogation for endoleak are believed necessary, supplanting standard abdominal radiologic and sonographic imaging. Endovascularly treated aneurysm has required conversion to open aneurysmectomy at a rate of 1% of cases during the first year in one reported study, increasing to 3.7% by the second year after implant. Conversion, far from being a benign procedure, carried a mortality risk approximating 25% irrespective of the reason for the graft failure.6
Apart from the conversion of endovascularly treated AAA to surgical resection, adjunctive interventions have been required to ensure aneurysm exclusion in 10% to 20% of cases. The types of adjunctive procedures used include stent-graft extensions for inadequate proximal or distal fixation sites or to correct separated modular attachments, endovascular occlusion of collateral sources of endoleak, and the stenting of the graft to correct obstructive twisting during deployment.
The importance of endovascular treatment of AAA should not be diminished by the demonstration of mid- and long-term problems occurring with first generation devices. Modifications to devices have been or are being made, under a regulatory controlled process, to specifically address the observations mentioned. Continuing clinical experience is defining the niche population appropriate for treatment with this modality, while the diagnostic tools to more accurately identify this patient cohort are being developed. The FDA undertakes an evaluation of risk versus benefit before issuing marketing approval for a device based on a global health care perspective. Whether a device meets the requirements for an individual patient is determined by a mélange of variables that include both the patient's vascular pathologic condition and systemic health and an educated estimate by the physician of the risks and benefits that this new therapy provides the patient compared with alternative treatments. The siren call of short-term advantage of endovascular treatment must be weighed against long-term costs (eg, monitoring requirements, adjunctive procedures). The health care practitioner, cognizant of the state of art for existing therapies, is the most competent to instruct the patient with an accurate informed consent for making the definitive decision.
The significant morbidity reduction and improved quality of life accompanying this less-invasive procedure can provide a treatment option for patients too ill to tolerate an open procedure. However, with operative mortality currently reported as similar for endovascular and open treatments of AAA, the risk of death, unlike perioperative morbidity, probably should not be a major consideration in deciding on treatment options for the individual patient.
The need exists at present, imposed by a risk of treatment failure, for indefinite postimplantation surveillance with imaging of endovascular grafts. This should enter into any decision to expand the indications for AAA treatment with this minimally invasive procedure. The intensity of monitoring an AAA of borderline size with abdominal ultrasound is far less onerous than that required at this time after endovascular treatment. This should also be a factor in decisions about endovascular treatment of younger patients when driven primarily by concerns for possible loss of sexual performance after an open procedure.
Endovascular procedures are foreign to the average vascular surgeon's experience and have a very definite learning curve. The FDA requires sponsors of approved endovascular grafts to conduct training programs to attenuate this learning curve. Credentialing committees of institutions introducing endovascular procedures should ensure that operators evaluated to perform this new procedure have participated in such training.
Endovascular treatment for AAA unquestionably offers a promising approach for addressing AAA occurring with increasing frequency in an aging population with its accompanying comorbidity. The physician with a clinical background and training in the treatment of vascular disease, as the vascular surgeon is, must take the lead in the further development of this therapeutic intervention and direct the inevitable expansion to the treatment of other manifestations of vascular disease.
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