Travoprost Intracameral Implant for Open-Angle Glaucoma or Ocular Hypertension: 12-Month Results of a Randomized, Double-Masked Trial.

INTRODUCTION: This prospective, multicenter, randomized, double-masked pivotal phase 3 trial evaluated the efficacy and safety of the travoprost intracameral SE-implant (slow-eluting implant, the intended commercial product) and FE-implant (fast-eluting implant, included primarily for masking purposes) compared to twice-daily (BID) timolol ophthalmic solution, 0.5% in patients with open-angle glaucoma (OAG) or ocular hypertension (OHT). METHODS: The trial enrolled adult patients with OAG or OHT with an unmedicated mean diurnal intraocular pressure (IOP) of ≥ 21 and unmedicated IOP ≤ 36 mmHg at each diurnal timepoint (8 A.M., 10 A.M., and 4 P.M.) at baseline. The eligible eye of each patient was administered an SE-implant, an FE-implant or had a sham administration procedure. Patients who received an implant were provided placebo eye drops to be administered BID and patients who had the sham procedure were provided timolol eye drops to be administered BID. The primary efficacy endpoint, for which the study was powered, was mean change from baseline IOP at 8 A.M. and 10 A.M. at day 10, week 6, and month 3. Non-inferiority was achieved if the upper 95% confidence interval (CI) on the difference in IOP change from baseline (implant minus timolol) was < 1.5 mmHg at all six timepoints and < 1 mmHg at three or more timepoints. The key secondary endpoint was mean change from baseline IOP at 8 A.M. and 10 A.M. at month 12. Non-inferiority at month 12 was achieved if the upper 95% CI was < 1.5 mmHg at both timepoints. Safety outcomes included treatment-emergent adverse events (TEAEs) and ophthalmic assessments. RESULTS: A total of 590 patients were enrolled at 45 sites and randomized to one of three treatment groups: 197 SE-implant (the intended commercial product), 200 FE-implant, and 193 timolol. The SE-implant was non-inferior to timolol eye drops in IOP lowering over the first 3 months, and was also non-inferior to timolol at months 6, 9, and 12. The FE-implant was non-inferior to timolol over the first 3 months, and also at months 6 and 9. Of those patients who were on glaucoma medication at screening, a significantly greater proportion of patients in the SE- and FE-implant groups (83.5% and 78.7%, respectively) compared to the timolol group (23.9%) were on fewer topical glaucoma medications at month 12 compared to screening (P < 0.0001, chi-square test). TEAEs, mostly mild, were reported in the study eyes of 39.5% of patients in the SE-implant group, 34.0% of patients in the FE-implant group and 20.1% of patients in the timolol group. CONCLUSIONS: The SE-travoprost intracameral implant demonstrated non-inferiority to timolol over 12 months whereas the FE-implant demonstrated non-inferiority over 9 months. Both implant models were safe and effective in IOP lowering in patients with OAG or OHT. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03519386.

Phase 3 Randomized Clinical Trial of the Safety and Efficacy of Travoprost Intraocular Implant in Patients with Open-Angle Glaucoma or Ocular Hypertension.

PURPOSE: To evaluate the safety and intraocular pressure (IOP)-lowering efficacy of 2 models of the travoprost intraocular implant (fast-eluting [FE] and slow-eluting [SE] types) from 1 of 2 phase 3 trials (the GC-010 trial). DESIGN: Multicenter, randomized, double-masked, sham-controlled, noninferiority trial. PARTICIPANTS: Patients with open-angle glaucoma or ocular hypertension having an unmedicated baseline mean diurnal IOP (average of 8 am, 10 am, and 4 pm time points) of ≥ 21 mmHg, and IOP of ≤ 36 mmHg at each of the 8 am, 10 am, and 4 pm timepoints at baseline. METHODS: Study eyes were randomized to the travoprost intraocular implant (FE implant [n = 200] or SE implant [n = 197] model) or to timolol ophthalmic solution 0.5% twice daily (n = 193). MAIN OUTCOME MEASURES: The primary outcome was mean change from baseline IOP in the study eye at 8 am and 10 am, at each of day 10, week 6, and month 3. Safety outcomes included adverse events (AEs) and ophthalmic assessments. RESULTS: Mean IOP reduction from baseline over the 6 time points ranged from 6.6 to 8.4 mmHg for the FE implant group, from 6.6 to 8.5 mmHg for the SE implant group, and from 6.5 to 7.7 mmHg for the timolol group. The primary efficacy end point was met; the upper limit of the 95% confidence interval of the difference between the implant groups and the timolol group was < 1 mmHg at all 6 time points. Study eye AEs, most of mild or moderate severity, were reported in 21.5%, 27.2%, and 10.8% of patients in the FE implant, SE implant, and timolol groups, respectively. The most common AEs included iritis (FE implant, 0.5%; SE implant, 5.1%), ocular hyperemia (FE implant, 3.0%; SE implant, 2.6%), reduced visual acuity (FE implant, 1.0%; SE implant, 4.1%; timolol, 0.5%), and IOP increased (FE implant, 3.5%; SE implant, 2.6%; timolol, 2.1%). One serious study eye AE occurred (endophthalmitis). CONCLUSIONS: The travoprost intraocular implant demonstrated robust IOP reduction over the 3-month primary efficacy evaluation period after a single administration. The IOP-lowering efficacy in both implant groups was statistically and clinically noninferior to that in the timolol group, with a favorable safety profile. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Systemic immunosuppression does not affect revascularization outcomes in patients with chronic limb-threatening ischemia.

OBJECTIVE: Many patients with chronic limb-threatening ischemia (CLTI) have additional comorbidities requiring systemic immunosuppression. Few studies have analyzed whether these medications may inhibit graft integration and effectiveness, or conversely, whether they may prevent inflammation and/or restenosis. Therefore, our study aim was to examine the effect of systemic immunosuppression vs no immunosuppression on outcomes after any first-time lower extremity revascularization for CLTI. METHODS: We identified all patients undergoing first-time infrainguinal bypass graft (BPG) or percutaneous transluminal angioplasty with or without stenting (PTA/S) for CLTI at our institution between 2005 and 2014. Patients were stratified by procedure type and immunosuppression status, defined as ≥6 weeks of any systemic immunosuppression therapy ongoing at the time of intervention. Immunosuppression vs nonimmunosuppression were the primary comparison groups in our analyses. Primary outcomes included perioperative complications, reintervention, primary patency, and limb salvage, with Kaplan-Meier and Cox proportional hazard models used for univariate and multivariate analyses, respectively. RESULTS: Among 1312 patients, 667 (51%) underwent BPG and 651 (49%) underwent PTA/S, of whom 65 (10%) and 95 (15%) were on systemic immunosuppression therapy, respectively. Whether assessing BPG or PTA/S patients, there were no differences noted in perioperative outcomes, including perioperative mortality, myocardial infarction, stroke, hematoma, or surgical site infection (P > .05). For BPG patients, Kaplan-Meier analysis and log-rank testing demonstrated no significant difference in three-year reintervention (37% vs 33% [control]; P = .75), major amputation (27% vs 15%; P = .64), or primary patency (72% vs 66%; P = .35) rates. Multivariate analysis via Cox regression confirmed these findings (immunosuppression hazard ratio [HR] for reintervention, 0.95; 95% CI, 0.56-1.60; P = .85; for major amputation, HR, 1.44; 95% CI, 0.70-2.96; P = .32; and for primary patency. HR, 0.97; 95% CI, 0.69-1.38; P = .88). For PTA/S patients, univariate analysis revealed similar rates of reintervention (37% vs 39% [control]; P = .57) and primary patency (59% vs 63%; P = .21); however, immunosuppressed patients had higher rates of major amputation (23% vs 12%; P = .01). After using Cox regression to adjust for baseline demographics, as well as operative and anatomic characteristics, immunosuppression was not associated with any differences in reintervention (HR, 0.75; 95% CI, 0.49-1.16; P = .20), major amputation (HR, 1.46; 95% CI, 0.81-2.62; P = .20), or primary patency (HR, 0.84; 95% CI, 0.59-1.19; P = .32). Sensitivity analyses for the differences in makeup of immunosuppression regimens (steroids vs other classes) did not alter the interpretation of any findings in either BPG or PTA/S cohorts. CONCLUSIONS: Our findings demonstrate that patients with chronic systemic immunosuppression, as compared with those who are not immunosuppressed, does not have a significant effect on late outcomes after lower extremity revascularization, as measured by primary patency, reintervention, or major amputation.

Pseudoaneurysm formation after Pasteurella multocida lower extremity vascular bypass graft infection.

Prosthetic vascular bypass graft infection is a rare complication requiring prompt identification and isolation of the organism. A 66-year-old woman developed left lower extremity pain and a pulsatile pseudoaneurysm 7 months after left common femoral to peroneal artery bypass with prosthetic polytetrafluoroethylene graft, requiring re-exploration and a jump graft. Pasteurella multocida was isolated from blood and tissue culture specimens, and the patient admitted to a new kitten that frequently bit her lower extremities. Treatment included intravenous administration of ertapenem for 6 weeks followed by lifelong oral antibiotic suppression, which may offer the best chance for limb salvage when total graft explantation would result in amputation.

Current issues and future directions for vascular surgery training from the results of the 2016-2017 and 2017-2018 Association of Program Directors in Vascular Surgery annual training survey.

BACKGROUND: Surgical training is constantly adapting to better prepare trainees for an evolving landscape of surgical practice. Training in vascular surgery additionally underwent a paradigm shift with the introduction of the integrated training pathway now more than a decade ago. With this study, we sought to characterize the needs and goals of our current vascular surgery trainee population. METHODS: The Association of Program Directors in Vascular Surgery Issues Committee compiled a survey to assess demographics, current needs, and goals of trainees and to evaluate trainee distress using a validated seven-item Physician Well-Being Index. The survey was distributed electronically to all current vascular surgery trainees and recent graduates in the academic years 2016-2017 and 2017-2018, and responses were recorded anonymously. RESULTS: During the 2 years of the survey, the response rate was 30% (n = 367/1196). The respondents were 55% (n = 202) integrated vascular residents and 45% (n = 165) vascular surgery fellows. In each year of the survey, 60% (n = 102/170) and 58% (n = 86/148) of trainees expressed a desire to pursue academics in their careers, whereas 37% (n = 63/174) and 35% (n = 53/152) indicated their program had structured academic development time (2016-2017 and 2017-2018, respectively). Fifty-five percent (n = 96/174) and 52% (n = 79/152) stated that the overall impact of collaborative learners was positive. More than 60% of respondents in both years of the survey indicated experiencing one or more symptoms of distress on a weekly basis. The frequency of distress was associated with older age and with the presence of an advanced degree in both years of the survey. Sex, level of training, presence of collaborative learners, and having protected research time were not associated with frequency of distress in either year of the survey. CONCLUSIONS: These results highlight an opportunity for programs to further evaluate the needs of their trainees for academic development during vascular surgery training to better accommodate trainees' career goals. Further investigation to identify modifiable risk factors for distress among vascular surgery trainees is warranted.

Complex endovascular aneurysm repair is associated with higher perioperative mortality but not late mortality compared with infrarenal endovascular aneurysm repair among octogenarians.

OBJECTIVE: As our collective experience with complex endovascular aneurysm repair (EVAR) has grown, an increasing number of older patients are being offered endovascular repair of juxtarenal aneurysms. Outcomes after complex EVAR in this older subpopulation are not well-described. We sought to specifically evaluate clinical outcomes after complex EVAR compared with infrarenal EVAR in a cohort of octogenarians. METHODS: A single-center retrospective review was conducted using a database of consecutive patients treated with elective EVAR for abdominal aortic aneurysms (AAAs) between 2009 and 2015. Only patients 80 years of age or older were included. Patients in the complex EVAR group were treated with either snorkel/chimney or fenestrated techniques, whereas infrarenal EVAR consisted of aneurysm repair without renal or visceral involvement. Relevant demographic, anatomic, and device variables, and clinical outcomes were collected. RESULTS: There were 103 patients (68 infrarenal, 35 complex) treated within the study period with a mean follow-up of 21 months. A total of 75 branch grafts were placed (59 renal, 11 celiac, 5 superior mesenteric artery) in the complex group, with a target vessel patency of 98.2% at latest follow-up. Patients undergoing complex EVAR were more likely to be male (82.8% vs 60.2%; P = .02) and have a higher prevalence of renal insufficiency (71.4% vs 44.2%; P = .008). The 30-day mortality was significantly greater in patients treated with complex EVAR (8.6% vs 0%; P = .03). There were no differences in major adverse events (P = .795) or late reintervention (P = .232) between groups. Interestingly, sac growth of more than 10 mm was noted to be more frequent with infrarenal EVAR (17.6% vs 2.8%; P = .039). However, both type IA (5.7% infrarenal; 4.9% complex) and type II endoleaks (32.3% infrarenal; 25.7% complex) were found to be equally common in both groups. Complex EVAR was not associated with increased all-cause mortality at latest follow-up (P = .322). Multivariable Cox modeling demonstrated that AAAs greater than 75 mm in diameter (hazard ratio; 4.9; 95% confidence interval, 4.6-48.2) and renal insufficiency (hazard ratio, 3.71; 95% confidence interval, 1.17-11.6) were the only independent risk factors of late death. CONCLUSIONS: Complex EVAR is associated with greater perioperative mortality compared with infrarenal EVAR among octogenarians. However, late outcomes, including the need for reintervention and all-cause mortality, are not significantly different. Larger aneurysms and chronic kidney disease portends greater risk of late death after EVAR, regardless of AAA complexity. These patient-related factors should be considered when offering endovascular treatment to older patients.

Is the abdominal aortic aneurysm rupture rate decreasing?

Decreased smoking has likely had the most significant impact on reducing the prevalence of AAAs. In a review of public data in England and Wales, Anjum and colleagues illustrated a reduction of AAA rupture from 1997 to2009 across all ages attributed to a concurrent decrease in prevalence of smoking. This trend has also been noted in a meta-analysis from Sweeting and colleagues and attributed to a reduction in the prevalence of smoking since the mid-1970s along with an enhanced awareness of cardiovascular risk factor reduction and selective aneurysm screening. Along with an effort to reduce AAA progression and rupture, tools to predict patient-specific risk of AAA rupture are evolving with refined models that incorporate both aneurysm wall stress and wall strength likely to provide the most promising approach. Although the role of statins, ACE inhibitors, beta-blockers, and aspirin in preventing or slowing aneurysmal rupture remains unresolved, their proven benefit in reducing long-term cardiovascular mortality suggests that these medications should be considered in any patient with a small AAA. Currently, randomized trials do not show any survival benefit for open or endovascular repair for small aneurysms in the range of 4.0 to 5.4 cm. AAA repair, whether through an endovascular or open approach, is not without potential complication. Even at centers of excellence, the 30-day mortality rate for conventional AAA surgery is 3% to 5%, with rates of major morbidityranging from 15% to 40%. The Society for Vascular Surgery guidelines recommends surveillance for patients with a fusiform AAA of 4.0 to 5.4 cm. The risk of AAA rupture appears to be decreasing through heightened public awareness, advanced technology for AAA detection, screening and surveillance, improved understanding of biomechanics and natural progression in AAA rupture, along with the availability of a wide range of medical therapies for risk factor reduction and minimally invasive options for AAA repair.

Suprarenal fixation barbs can induce renal artery occlusion in endovascular aortic aneurysm repair.

Renal artery occlusion following endovascular abdominal aortic aneurysm repair with suprarenal fixation is uncommon. We report one patient who was found to develop renal artery occlusion and parenchymal infarction 6 months after repair using an endovascular graft with suprarenal fixation. Our patient underwent emergent endovascular repair of a symptomatic 6 cm abdominal aortic aneurysm. The covered portion of the endograft was inadvertently deployed well below the renal artery orifices. At the completion of the procedure both renal arteries were confirmed to be patent. One month postoperatively, a computed tomographic (CT) scan showed exclusion of the aortic sac and normal enhancement of both kidneys. At 6 months, the patient was found to have elevated serum creatinine levels despite having no clinical symptoms. CT scanning revealed a nonenhancing left kidney, and angiography demonstrated an occlusion of the left renal artery. A barb welded to the bare metal stent appeared to be impinging on the renal artery. We believe that renal artery occlusion after endovascular repair can occur due to repetitive injury to the renal artery orifice from barbs welded to the bare metal stent. To our knowledge, this is the first reported case of renal artery occlusion caused by repetitive injury from transrenal fixation systems.