Mahmood K. Razavi

Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response

We have previously shown that a single portal vein infusion of a recombinant adeno-associated viral vector (rAAV) expressing canine Factor IX (F.IX) resulted in long-term expression of therapeutic levels of F.IX in dogs with severe hemophilia B. We carried out a phase 1/2 dose-escalation clinical study to extend this approach to humans with severe hemophilia B. rAAV-2 vector expressing human F.IX was infused through the hepatic artery into seven subjects. The data show that: (i) vector infusion at doses up to 2 × 1012 vg/kg was not associated with acute or long-lasting toxicity; (ii) therapeutic levels of F.IX were achieved at the highest dose tested; (iii) duration of expression at therapeutic levels was limited to a period of ∼8 weeks; (iv) a gradual decline in F.IX was accompanied by a transient asymptomatic elevation of liver transaminases that resolved without treatment. Further studies suggested that destruction of transduced hepatocytes by cell-mediated immunity targeting antigens of the AAV capsid caused both the decline in F.IX and the transient transaminitis. We conclude that rAAV-2 vectors can transduce human hepatocytes in vivo to result in therapeutically relevant levels of F.IX, but that future studies in humans may require immunomodulation to achieve long-term expression*.

Endovascular Stent–Graft Placement for the Treatment of Acute Aortic Dissection

BACKGROUND The standard treatment for acute aortic dissection is either surgical or medical therapy, depending on the morphologic features of the lesion and any associated complications. Irrespective of the form of treatment, the associated mortality and morbidity are considerable. METHODS We studied the placement of endovascular stent-grafts across the primary entry tear for the management of acute aortic dissection originating in the descending thoracic aorta. We evaluated the feasibility, safety, and effectiveness of transluminal stent-graft placement over the entry tear in 4 patients with acute type A aortic dissections (which involve the ascending aorta) and 15 patients with acute type B aortic dissections (which are confined to the descending aorta). Dissections involved aortic branches in 14 of the 19 patients (74 percent), and symptomatic compromise of multiple branch vessels was observed in 7 patients (37 percent). The stent-grafts were made of self-expanding stainless-steel covered with woven polyester or polytetrafluoroethylene material. RESULTS Placement of endovascular stent-grafts across the primary entry tears was technically successful in all 19 patients. Complete thrombosis of the thoracic aortic false lumen was achieved in 15 patients (79 percent), and partial thrombosis was achieved in 4 (21 percent). Revascularization of ischemic branch vessels, with subsequent relief of corresponding symptoms, occurred in 76 percent of the obstructed branches. Three of the 19 patients died within 30 days, for an early mortality rate of 16 percent (95 percent confidence interval, 0 to 32 percent). There were no deaths and no instances of aneurysm or aortic rupture during the subsequent average follow-up period of 13 months. CONCLUSIONS These initial results suggest that stent-graft coverage of the primary entry tear may be a promising new treatment for selected patients with acute aortic dissection. This technique requires further evaluation, however, to assess its therapeutic potential fully.

Endovascular Management of Iliac Vein Compression (May-Thurner) Syndrome

PURPOSE To evaluate the feasibility of endovascular techniques in treating venous outflow obstruction resulting from compression of the iliac vein by the iliac artery of the left lower extremity (May-Thurner syndrome). MATERIALS AND METHODS A retrospective analysis of 39 patients (29 women, 10 men; median age, 46 years) with iliac vein compression syndrome (IVCS) was performed. Nineteen patients presented with acute deep vein thrombosis (DVT) and 20 patients presented with chronic symptoms. All patients presented with leg edema or pain. In the acute group, patients were treated with catheter-directed thrombolysis (120,000-180,000 IU urokinase/h) and angioplasty followed by stent placement. In the chronic group, patients were treated with use of angioplasty and stent placement alone (n = 8), or in combination with thrombolysis (n = 12). Patients were then followed-up with duplex ultrasound and a quality-of-life assessment. RESULTS Initial technical success was achieved in 34 of 39 patients (87%). The overall patency rate at 1 year was 79%. Symptomatically, 85% of patients were completely or partially improved compared with findings before treatment. Thirty-five of 39 patients received stents. The 1-year patency rate for patients with acute symptoms who received stents was 91.6%; for patients with chronic symptoms who received stents, the 1-year patency rate was 93.9%. Five technical failures occurred. Major complications included acute iliac vein rethrombosis (< 24 hours) requiring reintervention (n = 2). Minor complications included perisheath hematomas (n = 4) and minor bleeding (n = 1). There were no deaths, pulmonary embolus, cerebral hemorrhage, or major bleeding complications. CONCLUSION Endovascular reconstruction of occluded iliac veins secondary to IVCS (May-Thurner) appears to be safe and effective.

Pelvic arterial embolization for control of obstetric hemorrhage: A five-year experience☆☆☆

OBJECTIVE Obstetric hemorrhage is a significant cause of maternal morbidity and death. Postpartum hemorrhage that cannot be controlled by local measures has traditionally been managed by bilateral uterine artery or hypogastric artery ligation. These techniques have a high failure rate, often resulting in hysterectomy. In contrast, endovascular embolization techniques have a success rate of >90%. An additional benefit of the latter procedure is that fertility is maintained. We report our experience at Stanford University Medical Center in which this technique was used in 6 cases within the past 5 years. STUDY DESIGN Six women between the ages of 18 and 41 years underwent placement of arterial catheters for emergency (n = 3) or prophylactic (n = 3) control of postpartum bleeding. Specific diagnoses included cervical pregnancy (n = 1), uterine atony (n = 3), and placenta previa and accreta (n = 2). RESULTS Control of severe or anticipated postpartum hemorrhage was obtained with transcatheter embolization in 4 patients. A fifth patient had balloon occlusion of the uterine artery performed prophylactically, but embolization was not necessary. In a sixth case, bleeding could not be controlled in time, and hysterectomy was performed. The only complication observed with this technique was postpartum fever in 1 patient, which was treated with antibiotics and resolved within 7 days. CONCLUSIONS Uterine artery embolization is a superior first-line alternative to surgery for control of obstetric hemorrhage. Use of transcatheter occlusion balloons before embolization allows timely control of bleeding and permits complete embolization of the uterine arteries and hemostasis. Given the improved ultrasonography techniques, diagnosis of some potential high-risk conditions for postpartum hemorrhage, such as placenta previa or accreta, can be made prenatally. The patient can then be prepared with prophylactic placement of arterial catheters, and rapid occlusion of these vessels can be achieved if necessary.

Percutaneous balloon fenestration and stenting for life-threatening ischemic complications in patients with acute aortic dissection

OBJECTIVES Acute aortic dissection frequently causes life-threatening ischemia of end-organs, historically associated with mortality exceeding 60%. Reperfusion with the use of interventional radiologic methods has evolved as a promising treatment. We report results of our initial 6 years of experience with percutaneous balloon fenestration of the intimal flap and endovascular stenting. METHODS Forty patients (32 male and 8 female) with a median age of 53 years (range 16-86 years) underwent percutaneous treatment for peripheral ischemic complications of 10 type A and 30 type B acute aortic dissections since 1991. Twenty patients had ischemia of multiple organ systems. Thirty patients had renal, 22 had leg, 18 had mesenteric, and 1 had arm ischemia. RESULTS Fourteen patients were treated with stenting of either the true or false lumen combined with balloon fenestration of the intimal flap, 24 with stenting alone, and 2 with fenestration alone. Successful revascularization was achieved in 93% +/- 4% (+/-70% confidence levels) of patients (37/40). Nine patients had procedure-related complications. The 30-day mortality rate was 25% +/- 7% (10/40), often related to irreversible ischemia of intra-abdominal organs that was present before the procedure. Of the remaining 30 patients, 5 have died and the remaining 25 continue to have relief of ischemic symptoms at a mean follow-up of 29 months. CONCLUSION Percutaneous balloon fenestration of the intimal flap and endovascular stenting is an effective treatment for life-threatening ischemic complications of acute aortic dissection.

MYCOTIC ANEURYSMS OF THE THORACIC AORTA : REPAIR WITH USE OF ENDOVASCULAR STENT-GRAFTS

PURPOSE Standard therapy of mycotic aneurysms in the descending aorta consists of thoracotomy and in situ graft placement or extraanatomic bypass. The alternative use of endovascular stent-grafts was evaluated for management of infected aneurysms of the thoracic aorta. MATERIALS AND METHODS In a retrospective analysis during a 5-year period, 112 patients underwent stent-graft placement for thoracic aortic aneurysms. Three patients (mean age, 68.6; range, 64-70 years) had mycotic thoracic aneurysms. Stent-grafts were constructed from Z stents covered with polyester fabric and were delivered remotely through a catheter under fluoroscopic guidance. RESULTS Complete thrombosis of the mycotic aneurysms was achieved in all patients. One patient required a second separate stent-graft placement procedure because of migration of the initial device; the second patient underwent surgical repair of a ruptured mycotic abdominal aortic aneurysm followed immediately by stent-graft placement for a chronic mycotic thoracic aneurysm; a third patient underwent repair of two infected false aneurysms secondary to complete rupture of a surgical interposition graft. There were no complications of persistent bacteremia despite placement of the stent-graft device at the site of primary infection, reinfection, delayed rupture, paraplegia, distal emboli, or surgical conversion. One patient died of cardiac arrest at 25 months; there were no perioperative deaths (< or = 30 days). The remaining two patients were alive and well at median follow-up of 24 months (range, 4-25 months). CONCLUSION Endovascular stent-grafts combined with antibiotic therapy may be an alternative to conventional thoracotomy in managing mycotic aneurysms of the descending thoracic aorta.

Internal Iliac Artery Embolization in the Stent-Graft Treatment of Aortoiliac Aneurysms: Analysis of Outcomes and Complications

PURPOSE To analyze the complications of internal iliac artery (IIA) embolization in conjunction with stent-graft treatment of aortoiliac aneurysms. MATERIALS AND METHODS Seventy-one patients with aortoiliac ( n = 47) or iliac ( n = 24) aneurysms were treated with endoluminal placement of stent-grafts. Thirty-two patients (31 men, one woman; mean age, 73 years; range, 56–88 years) had embolization or occlusion of one ( n = 27) or both ( n = 5) IIAs. Status of the IIAs and the collateral circulation was assessed by retrospective review of angiographic images. Follow-up consisted of a standardized patient questionnaire and review of radiologic and medical records. RESULTS The mean follow-up time was 35 months (range, 5–64 months). Eleven of the 47 patients with abdominal aortic aneurysms (AAA) (23%) and 19 of the 24 patients with iliac aneurysms (79%) required IIA embolization. One patient with AAA and another with iliac aneurysm had unintentional occlusion of an IIA by extension of the stent-graft over their origins. A total of seven patients had bilateral occlusion of the IIAs after the procedure. Additionally, the inferior mesenteric arteries (IMAs) of two other patients with AAA were also embolized. In six patients, all three vessels were occluded after placement of the stent-grafts. Symptoms were reported in nine of the 20 (45%) patients with iliac aneurysms and in three of the 12 (25%) patients with AAA. Symptoms consisted of buttock claudication (nine of 32, 28%), new sexual dysfunction (two of 16, 12%), and transient urinary retention (3%). Seven of the claudicants had resolution of symptoms after a mean interval of 14 months (range, 1–36 months). There were no instances of bowel ischemia, neurologic sequelae, or buttock necrosis related to these procedures. CONCLUSION Embolization of the IIA is associated with symptoms in a significant number of patients. While symptoms are transient in most patients, they can be problematic. Efforts should be made to preserve the pelvic circulation if possible.

Quality improvement guidelines for the treatment of lower-extremity deep vein thrombosis with use of endovascular thrombus removal.

Suresh Vedantham, MD, Patricia E. Thorpe, MD, John F. Cardella, MD, Chair, Clement J. Grassi, MD, Nilesh H. Patel, MD, Hector Ferral, MD, Lawrence V. Hofmann, MD, Bertrand M. Janne d’Othée, MD, Vittorio P. Antonaci, MD, Elias N. Brountzos, MD, Daniel B. Brown, MD, Louis G. Martin, MD, Alan H. Matsumoto, MD, Steven G. Meranze, MD, Donald L. Miller, MD, Steven F. Millward, MD, Robert J. Min, MD, Calvin D. Neithamer Jr., MD, Dheeraj K. Rajan, MD, Kenneth S. Rholl, MD, Marc S. Schwartzberg, MD, Timothy L. Swan, MD, Richard B. Towbin, MD, Bret N. Wiechmann, MD, and David Sacks, MD, for the CIRSE and SIR Standards of Practice Committees

Rationale and design of the ATTRACT Study: A multicenter randomized trial to evaluate pharmacomechanical catheter-directed thrombolysis for the prevention of postthrombotic syndrome in patients with proximal deep vein thrombosis

BACKGROUND Current standard therapy for patients with acute proximal deep vein thrombosis (DVT) consists of anticoagulant therapy and graduated elastic compression stockings. Despite use of this strategy, the postthrombotic syndrome (PTS) develops frequently, causes substantial patient disability, and impairs quality of life. Pharmacomechanical catheter-directed thrombolysis (PCDT), which rapidly removes acute venous thrombus, may reduce the frequency of PTS. However, this hypothesis has not been tested in a large multicenter randomized trial. STUDY DESIGN The ATTRACT Study is an ongoing National Institutes of Health-sponsored, Phase III, multicenter, randomized, open-label, assessor-blinded, parallel two-arm, controlled clinical trial. Approximately 692 patients with acute proximal DVT involving the femoral, common femoral, and/or iliac vein are being randomized to receive PCDT + standard therapy versus standard therapy alone. The primary study hypothesis is that PCDT will reduce the proportion of patients who develop PTS within 2 years by one-third, assessed using the Villalta Scale. Secondary outcomes include safety, general and venous disease-specific quality of life, relief of early pain and swelling, and cost-effectiveness. CONCLUSION ATTRACT will determine if PCDT should be routinely used to prevent PTS in patients with symptomatic proximal DVT above the popliteal vein.

Stent-graft therapy for subclavian artery aneurysms and fistulas: single-center mid-term results.

PURPOSE To evaluate the potential of covered stents to replace surgery in the treatment of subclavian artery aneurysms and traumatic injuries. MATERIALS AND METHODS Nine patients (five men, four women; age range, 20-83 years; mean, 54 years) with subclavian artery aneurysms (n = 5) or fistulas (n = 4) were treated with stent-grafts. All devices used were custom-made, consisting of polytetrafluoroethylene (PTFE)-covered Palmaz (n = 5), Wallstent (n = 2), Z stents (n = 8), or a polyester-covered Z stent (n = 1). One patient was lost to follow-up after 2 months. All others were followed up with clinical evaluation, computed tomography (CT), and/or ultrasound. RESULTS All devices were deployed successfully with exclusion of the aneurysms and fistulas. There were two procedure-related complications (22%), consisting of groin pseudoaneurysms requiring surgical repair 3 and 9 days after the procedure. One of those patients required additional oral antibiotic therapy for a postsurgical groin wound infection. One patient developed a stenosis at 12 months, which required angioplasty. The stent-graft thrombosed in one patient because of a kink 2 months after placement, which was successfully treated by thrombolysis and placement of a Wallstent. The primary and secondary patencies are 89% and 100%, respectively, after a mean follow-up of 29 months (2-66 mo). CONCLUSION Mid-term results of stent-graft therapy of subclavian artery aneurysms and fistulas are encouraging, with low morbidity and excellent clinical outcome.