Review of Previous and Current Clinical Trials
Currently, there are several thoracic endografts available for the treatment of descending thoracic aortic aneurysms. They are the TAG device made by WL Gore (Flagstaff, Arizona), the TX2 device by Cook, Inc. (Bloomington, Indiana), the Talent and Valiant devices by Medtronic (Santa Rosa, California), and the Relay device by Bolton Medical (Sunrise, Florida). At this time, the only thoracic endograft approved by the FDA for use in the United States is the TAG device. The TX2 device and Talent device have completed their initial enrollment and have been submitted to the U.S. Food and Drug Administration (FDA) for approval. They are expected to gain FDA approval in late 2007 or early 2008. The Valiant and Relay devices are also in clinical trial and currently enrolling patients. Tables 1 and 2 list both the inclusion and exclusion criteria, respectively, for each of the major trials.
TAG Device (WL Gore and Associates)
The TAG device is a symmetrical expanded PTFE tube with an external nitinol self-expanding stent along the entire graft surface. A circumferential PTFE sealing cuff is located on the external surface of the endograft at the base of each flared, scalloped end. This device is currently the only device commercially available at this time.
The TAG device was investigated in the Pivotal trial completed in 2001. This was a nonrandomized, controlled clinical trial. There were two arms in the study. The first arm was the control group, which consisted of 94 patients treated by open surgical repair. The second arm was the device treatment group, which consisted of 142 patients treated with the TAG device. As shown in Table 1, at least 2 cm of the normal descending thoracic aorta was required distal to the left common carotid artery and proximal to the celiac artery in order to be enrolled in the trial. A left subclavian artery revascularization procedure was mandated by the trial design.
Of the 142 patients, 139 (98%) had a successful implantation of the device. The 3 failures were attributed to inadequate arterial access. The mean size of the treated descending thoracic aneurysm was 64.1 ± 15.4 mm. The average age of patients treated was 71 years. The majority of the patients were male (57.7%). Single graft therapy was achieved in 44% of patients and the additional 56% of patients required two or more devices to exclude the aneurysm. Of the patients 90% were American Society of Anesthesiologists category III or IV. In 28 patients, repair of the aneurysm required covering the left subclavian artery.
The procedure time averaged 150 minutes, and the estimated blood loss averaged 506 ml for the endovascular treatment arm. The post-procedure hospital stay for the TAG device patients averaged 7.6 days, with an average of 2.6 days in the intensive care unit. The 30-day morbidity rate was 32%, which included 45 patients who had at least 1 adverse event. Of those 45 patients, 5 (4% of the total patient pool) experienced a stroke, 4 (3%) demonstrated temporary or permanent paraplegia, 20 (14%) experienced vascular trauma or thrombosis, and 2 (1.5%) died.
The mean length of follow-up was 24 months. Four of the patients had aneurysm-related deaths during this period. Three patients underwent endovascular procedures to correct endoleaks. No ruptures were reported. Of note, 20 wire fractures were identified in 19 patients (13%). Of these wire fractures, 18 (90%) occurred in the longitudinal spine, and only 1 patient required treatment, due to a type 3 endoleak. At 2 years, aneurysm-related and overall survival rates were 97% and 75%, respectively. Of the three patients that expired within the first 30 days, one death was secondary to a postoperative stroke. The second death was attributed to a cardiac event on postoperative day 11. A third death occurred outside the 30-day period, but during the same admission after a long hospital course (7 months), secondary to anoxic brain injury after a respiratory arrest. In comparison, 6 (6.4%) deaths occurred in the surgical control group. Spinal cord ischemia (SCI) was noted in 4 patients in the TAG group (3%). Three patients recovered function, but one patient’s deficit persisted. In the surgical control group, the incidence of SCI was significantly higher at 14%. Cerebrovascular incidents were equal among the two groups, both at 4.3%. Endoleaks occurred in 5 (3%) of the TAG patients. Vascular injury in the TAG group was higher at 14% as compared to 4% in the open surgical group. This significantly higher rate of vascular injury was associated with the passage of large introducer sheaths through the iliac arteries. A comparison of complications is illustrated in Figure 1.
As stated earlier, there were 20 wire fractures in the original TAG device (99-01) in the Pivotal trial and 19 of these were in the longitudinal spine. This prompted a redesign of the TAG device, which included the removal of the longitudinal spine and the addition of a low permeability film layer. These changes provide longitudinal stiffness for deployment accuracy and the change is also an attempt to decrease the permeability of the device and prevent endotension. Below is a picture of both the original and the modified TAG devices. (Figure 2)
The modified device (TAG 03-03) was then evaluated in the TAG Confirmatory trial. The Confirmatory trial consisted of 51 patients treated with the Modified Tag Device and the open surgical controls were used from the original Pivotal Trial (99-01). The 51 patients were enrolled by June 2004 and the 5-year follow up is currently ongoing.
The currently available follow-up data for both the original TAG Graft and the Modified TAG Endograft demonstrate that at 5 and 2 years, respectively, the TAG devices provide a survival advantage from aneurysm-related death with 98% of the TAG patients surviving as compared to 90% of the open controls. This is illustrated in Figure 3. The Pivotal trial with the original device is labeled as 99-01, the modified TAG device is labeled as 03-03, and the treatment IDE (continued access for investigators until PMA approval) is labeled as 04-02.
Also, freedom from major adverse events (MAE) was better for the TAG endograft devices compared to the open surgical controls. At two years, 63% of the TAG modified device patients were free from MAEs. At 5 years, 37% of patients with the Original TAG device were free from MAEs. Only 21% of patients were free from MAEs in the surgical control group. These results are represented in Figure 4.
Although the TAG endograft has fewer MAEs and the aneurysm-related death is lower then the open controls, the overall patient mortality rate from all causes for the original TAG device and open surgical repair is similar at around 27%. The modified TAG has a decreased mortality rate at 2 years, as compared to the open surgical controls, however, it remains to be seen if this survival advantage will continue out to 5 years (Figure 5).
Currently, there is a 45 mm GORE TAG Device Trial that has gained approval by the FDA for initiation of a clinical trial. The first patient will be enrolled in the winter of 2007, and the trial is designed to enroll 35 patients. The planned follow up is 5 years.
Talent Thoracic Device (Medtronic)
The Medtronic Talent thoracic endograft device was initially manufactured by World Medical Corporation and was subsequently acquired by the Medtronic Corporation. In its current state, it is a polyester graft with fabric sewn to a self-expanding nitinol wire frame. The device is modular and accommodates the use of additional main sections as well as proximal and distal extensions. The Talent device has completed enrollment in the Valsartan/HCTZ Combination Therapy in Patients with Moderate to Severe Systolic Hypertension (VALOR) trial.
The primary objective of the VALOR trial is to determine the safety and efficacy of the Talent endograft in the treatment of descending thoracic aneurysms in patients who would also be candidates for open repair. The study will compare the overall mortality of thoracic aneurysm repair to the overall mortality rate of open repair, as reported in the literature. Additional safety and efficacy data to be reported will include technical success rate, the percentage of major adverse events, device related events, and aneurysm rupture rates at 30 days and at 12 months. Other data analysis will include blood loss, blood product transfusion, operative time, ICU stay, and overall length of hospital stay. The VALOR trial started enrollment in 2003 and recently completed the one-year follow up in 2006. The inclusion and exclusion criterion are listed in Tables 1 and 2, respectively.
Results for the 150 patients in the high-risk group have been presented. Mean age of the enrolled patients was 73 years old, with a male to female ratio of 1.5: 1. The thoracic aortic pathology treated included: descending thoracic aneurysms (82%), dissecting aneurysms (9%), pseuodaneurysm (9%), traumatic injury (6%), and complicated type B dissection (4%). Initial technical success rate was achieved in 98% of the patients. The mortality rate at 30 days was 8.4%. The stroke rate was 8%. The rate of paraplegia/paraparesis was 5.5% and two-thirds of the patients recovered by 6 months. The reported endoleak rate was 12% at 1 month and 10% at 6 months, with no ruptures, conversions, device migrations, or graft thromboses. Secondary interventions were performed in 2.8% of patients at 6 months.
Valiant Thoracic Device (Medtronic)
Medtronic also has a third generation device, the Valiant thoracic stent graft. This is similar to the Talent thoracic stent graft in design and materials. Both devices are made of self-expanding, nitinol wire scaffolding attached to a low-profile polyester monofilament weave. However, the Valiant endograft device has some design changes as compared to the Talent device. First, the longitudinal connecting bar was removed. Second, the proximal and distal attachment springs were redesigned to be smaller and to distribute the attachment point force more equally. Third, the nitinol springs are attached to the outer surface of the graft to allow for better surface attachment and tissue incorporation. This device will be tested in the VALOR II trial, which started enrolling patients in December 2006.
TX2 Device (Cook, Inc.)
The Cook thoracic endograft is constructed from Dacron fabric sewn with braided polyester and monofilament polypropylene sutures to self-expanding stainless steel Z-stents. The device comes in two variants. The TX1 is a one-piece standalone graft. The TX2 is a two-piece modular device. The proximal portion (TX2P) is covered and includes 5-mm-long, caudally oriented barbs to prevent distal migration. The distal portion (TX2D) has a two-stent overlap zone in which the stents are internalized and an uncovered Gianturco Z-stent distally to help prevent proximal migration.
The Zenith TX2 device is being tested clinically in the STARZ-TX2 trial. The inclusion and exclusion criteria (Table 1 and Table 2) are similar to the TAG and Talent/Valiant trials, with the one exception. A 30 mm landing zone distal to the left common carotid artery and proximal to the celiac artery are required as opposed to 20 mm for the other devices. This trial started enrollment in March 2003 with a target enrollment of 135 patients to be treated with the TX2 device and 70 patients as open surgical controls. Enrollment was completed in July 2006 with 160 patients treated.
Preliminary results of the TX2 pivotal trial were presented at the 2007 Society for Vascular Surgery meeting. The clinical trial of the TX2 device consisted of 160 patients treated with TEVAR and 70 control patients treated with open repair. In the TEVAR group, 72% of the patients were male, as compared to 60% of the control group. The mean age of patients in the TEVAR group was 72 years old, compared to 68 years old for the open repair group. The defined clinical utility measures for the study reported at this time are as follows: Intraoperative red blood cell transfusion in the TEVAR group was 3% versus 87% as compared to the open surgical controls. The average days to hospital discharge was 5.0 in the TEVAR group and 21.4 in the control group. Perioperative mortality was 1.9% in the TEVAR group, as compared to 5.7% in the open control. The rate of stroke in the TEVAR group was 2.5% versus 7.1% in the open group. Paraplegia was noted in 1.3% of the TEVAR patients and 5.7% of the open surgical patients. Finally, renal failure requiring dialysis was noted in 1.3% versus 4.3% in the control group. The morbidity and mortality percentages for both groups are compared in Figure 6. The trial data are currently being reviewed and FDA approval is anticipated in late 2007.
Relay Device (Bolton Medical)
The Relay device created by Bolton Medical consists of self-expanding nitinol stents sutured to a polyester fabric graft. The nickel titanium stents are sinusoidal in shape and are serially placed along the length of the polyester graft fabric. An additional curved nitinol wire is sutured to the outer curve of the endograft to provide longitudinal support.
This device has currently completed phase 1 of the safety trials and has commenced a pivotal trial. The phase 1 study for the Relay device as of November 2005 had enrolled 20 patients, 18 with thoracic aortic aneurysms and 2 with penetrating ulcers. Technical success was achieved in all but 3 cases. In the remaining 17 successful deployments, the aneurysms were angiographically excluded 100% of the time (Figure 7).
Thoracic aortic aneurysms are difficult clinical problems. There is a significant morbidity and mortality associated with the traditional open repair. In the last 10 years, a less invasive endovascular approach to repair TAAs has surfaced. Currently, there is one device that is FDA-approved and four devices in clinical trial. The W.L. Gore TAG device has received FDA approval and in turn both the TX2 by Cook, Inc., and the Talent graft by Medtronic will soon likely receive approval. The Valiant graft by Medtronic is already in use in European countries and one can reasonably assume that after completing its enrollment in the VALOR II trial, it will also soon thereafter receive approval in the United States. The Relay device by Bolton Medical has finished its phase 1 trial and has started a pivotal trial.
These devices have shown great potential in improving the treatment of descending thoracic aneurysms. They have improved both the perioperative morbidity and mortality of descending thoracic aneurysm repair and are leading a paradigm shift in the way we think about the treatment of these aneurysms and other aortic pathologies. These preliminary studies have been so successful that investigators have already begun to use these devices and modifications of these devices in high-risk patients for other disease processes, such as aortic dissection and traumatic disruption.
In the near future, clinicians will have many endograft choices for the treatment of DTAs. Also, as the indications for thoracic stent grafts expand, there will be new devices designed and redesigned to target the specific disease process. Currently, the endovascular repair of thoracic aneurysms shows great promise, and it will be interesting and exciting to see how the next generation of devices affect and improve the treatment of these aneurysms and more complex thoracic aortic pathology.