Objectives The aim of this study was to analyze the CAPTURE 2 (Carotid ACCULINK/ACCUNET Post Approval Trial to Uncover Rare Events) study for physician- or site-related variables associated with ...differential outcomes for carotid artery stenting (CAS). Background The CAPTURE 2 trial is an ongoing, prospective, nonrandomized, independently adjudicated, multicenter clinical study enrolling high-surgical-risk patients undergoing CAS. Methods In this assessment of the CAPTURE 2 study, the American Heart Association carotid endarterectomy guideline limits were used to define acceptable site and physician CAS outcomes; therefore, the resulting population of nonoctogenarian, asymptomatic subjects in this analysis is confined to 3,388 (of the total 5,297) subjects treated at 180 U.S. hospitals by 459 operators between March 2006 and January 2009. Results The rates of death, stroke, and myocardial infarction and death and stroke (DS) at 30 days were 3.5% and 3.3%, respectively, for the full CAPTURE 2 study cohort and 2.9% and 2.7%, respectively, for the asymptomatic, nonoctogenarian subgroup. In this subgroup, two-thirds of sites (118 of 180, 66%) had no DS events. Within the remaining sites, an inverse relationship between event rates and hospital patient volume as well as between event rates and individual operator volume was observed. The DS rates trended lower for interventional cardiologists compared with other specialties. Conclusions Outcomes from the largest prospectively gathered, independently adjudicated, multicenter CAS study indicate that CAS can be safely performed in a variety of hospital settings by physicians with various specialties. The most important determinant of perioperative CAS outcomes was both site and operator CAS volume. A threshold of 72 cases was found to be necessary for consistently achieving a DS rate below 3% in this later-phase single arm study; background era and non-study operator experience will affect this determination. (Second Phase of “Carotid RX ACCULINK/RX ACCUNET Post-Approval Trial to Uncover Unanticipated or Rare Events”; NCT00302237 )
Abstract Background In EVEREST II (Endovascular Valve Edge-to-Edge Repair Study), treatment of mitral regurgitation (MR) with a novel percutaneous device showed superior safety compared with surgery, ...but less effective reduction in MR at 1 year. Objectives This study sought to evaluate the final 5-year clinical outcomes and durability of percutaneous mitral valve (MV) repair with the MitraClip device compared with conventional MV surgery. Methods Patients with grade 3+ or 4+ MR were randomly assigned to percutaneous repair with the device or conventional MV surgery in a 2:1 ratio (178:80). Patients prospectively consented to 5 years of follow-up. Results At 5 years, the rate of the composite endpoint of freedom from death, surgery, or 3+ or 4+ MR in the as-treated population was 44.2% versus 64.3% in the percutaneous repair and surgical groups, respectively (p = 0.01). The difference was driven by increased rates of 3+ to 4+ MR (12.3% vs. 1.8%; p = 0.02) and surgery (27.9% vs. 8.9%; p = 0.003) with percutaneous repair. After percutaneous repair, 78% of surgeries occurred within the first 6 months. Beyond 6 months, rates of surgery and moderate-to-severe MR were comparable between groups. Five-year mortality rates were 20.8% and 26.8% (p = 0.4) for percutaneous repair and surgery, respectively. In multivariable analysis, treatment strategy was not associated with survival. Conclusions Patients treated with percutaneous repair more commonly required surgery for residual MR during the first year after treatment, but between 1- and 5-year follow-up, comparably low rates of surgery for MV dysfunction with either percutaneous or surgical therapy endorse the durability of MR reduction with both repair techniques. (EVEREST II Pivotal Study High Risk Registry; NCT00209274 )
Abstract Background Surgical mitral valve repair (SMVR) remains the gold standard for severe degenerative mitral regurgitation (DMR). However, the results with transcatheter mitral valve repair ...(TMVR) in prohibitive-risk DMR patients have not been previously reported. Objectives This study aimed to evaluate treatment of mitral regurgitation (MR) in patients with severe DMR at prohibitive surgical risk undergoing TMVR. Methods A prohibitive-risk DMR cohort was identified by a multidisciplinary heart team that retrospectively evaluated high-risk DMR patients enrolled in the EVEREST (Endovascular Valve Edge-to-Edge Repair Study) II studies. Results A total of 141 high-risk DMR patients were consecutively enrolled; 127 of these patients were retrospectively identified as meeting the definition of prohibitive risk and had 1-year follow-up (median: 1.47 years) available. Patients were elderly (mean age: 82.4 years), severely symptomatic (87% New York Heart Association class III/IV), and at prohibitive surgical risk (STS score: 13.2 ± 7.3%). TMVR (MitraClip) was successfully performed in 95.3%; hospital stay was 2.9 ± 3.1 days. Major adverse events at 30 days included death in 6.3%, myocardial infarction in 0.8%, and stroke in 2.4%. Through 1 year, there were a total of 30 deaths (23.6%), with no survival difference between patients discharged with MR ≤1+ or MR 2+. At 1 year, the majority of surviving patients (82.9%) remained MR ≤2+ at 1 year, and 86.9% were in New York Heart Association functional class I or II. Left ventricular end-diastolic volume decreased (from 125.1 ± 40.1 ml to 108.5 ± 37.9 ml; p < 0.0001 n = 69 survivors with paired data). SF-36 quality-of-life scores improved and hospitalizations for heart failure were reduced in patients whose MR was reduced. Conclusions TMVR in prohibitive surgical risk patients is associated with safety and good clinical outcomes, including decreases in rehospitalization, functional improvements, and favorable ventricular remodeling, at 1 year. (Real World Expanded Multi-center Study of the MitraClip System REALISM; NCT01931956 )
To assess safety and efficacy of the S.M.A.R.T. Vascular Stent System (Cordis Corp, Fremont, California) in obstructive superficial femoral artery (SFA) disease.
The single-arm, multicenter STROLL ...study (S.M.A.R.T. Nitinol Self-Expanding Stent in the Treatment of Obstructive Superficial Femoral Artery Disease) included 250 patients (250 lesions in SFA or proximal popliteal artery). The efficacy endpoint was primary patency defined by freedom from binary restenosis (peak systolic velocity ratio > 2.5) as derived by duplex ultrasound plus clinically driven target lesion revascularization (TLR) at 12 months.
Mean age of patients was 67.7 years ± 10.3; 47.2% of patients had diabetes; distribution of Rutherford/Becker classes 2, 3, and 4 was 45.8%, 51.4%, and 2.8%. Mean lesion length and reference vessel diameter were 77.3 mm ± 35.3 and 4.9 mm ± 0.7, respectively (23.6% cases with total occlusions). The 30-day freedom from major adverse events (death, index limb amputation, clinically driven TLR) was 100%. The 1-year primary patency was 81.7% by Kaplan-Meier estimate. The presence of diabetes or total occlusion had no effect on primary patency. Ankle-brachial index was 0.4-0.8 in 84.6% of patients at baseline and improved to > 0.8 in 81.0% of patients at 12 months. The proportion of patients in Rutherford/Becker class 3-4 was reduced from 54.2% at baseline to 8.0% at 12 months. Four patients (2.0%) experienced single-stent strut fracture (type I) at 1 year, without associated loss of stent patency.
The S.M.A.R.T. Vascular Stent System proved to be safe and effective for endovascular treatment of obstructive SFA and proximal popliteal artery disease, based on 1-year vessel patency and associated hemodynamic and clinical improvements.
Percutaneous mitral repair is rapidly developing as an alternative to cardiac surgery in select patients. The Evalve percutaneous E2E system uses the MitraClip to replicate the surgical suture-based ...approach. This procedure requires real-time echocardiographic guidance in a unique and significant collaboration between echocardiographer and interventionalist. transesophageal echocardiography (TEE) is used as the primary imaging modality to guide this procedure and is essential to its success.
In EVEREST I, the US multicenter phase I safety and feasibility trial, 47 patients with 3 or 4+ mitral regurgitation (MR) were enrolled. The trial involved a standardized echocardiographic imaging protocol with a standardized anatomic-based vocabulary, predetermined standard TEE views, preprocedural strategy meetings, and display of echocardiographic aids to optimize communication and procedural efficiency during placement of the clip.
TEE guidance facilitated the creation of a double-orifice mitral valve in all 47 patients enrolled (100%), and 40 patients were discharged with 1 or more clips (85%). At discharge, successful placement of a clip and <or= 2+ MR was present in 34 patients (74%). The standardized approach contributed to a reduction in the time to perform the procedure over the course of the trial at both initial and new sites.
TEE is essential to the guidance of percutaneous MitraClip E2E repair. A streamlined approach to echocardiographic guidance, using predetermined standardized views, a common anatomic-based vocabulary, preprocedural strategy meetings, and a display of echocardiographic aids in the catheterization laboratory shortens the procedure time and allows for efficient percutaneous repair.
Summary Background The 2014 Zaire Ebola virus outbreak highlighted the need for a safe, effective vaccine with a rapid onset of protection. We report the safety and immunogenicity of the recombinant ...vesicular stomatitis virus-Zaire Ebola virus envelope glycoprotein vaccine (rVSV∆G-ZEBOV-GP) across a 6 log10 dose range in two sequential cohorts. Methods In this phase 1b double-blind, placebo-controlled, dose-response study we enrolled and randomly assigned healthy adults (aged 18–61 years) at eight study sites in the USA to receive a single injection of vaccine or placebo, administered by intramuscular injection. In cohort 1, participants were assigned to receive 3 × 103 , 3 × 104 , 3 × 105 , or 3 × 106 PFU doses of rVSV∆G-ZEBOV-GP or placebo. In cohort 2, participants were assigned to receive 3 × 106 , 9 × 106 , 2 × 107 , or 1 × 108 PFU doses of rVSV∆G-ZEBOV-GP or placebo. Participants were centrally allocated by the study statistician to vaccine groups or placebo through computer-generated randomisation lists. The primary safety outcome was incidence of adverse events within 14 days in the modified intention-to-treat population (all randomly assigned participants who received vaccine or placebo), and the primary outcome for immunogenicity was IgG ELISA antibody titres at day 28 in the per-protocol population. Surveillance was enhanced for arthritis and dermatitis through to day 56. This study is registered with ClinicalTrials.gov , number NCT02314923. Findings Between Dec 26, 2014, and June 8, 2015, 513 participants were enrolled and randomly assigned; one was not immunised because of unsuccessful phlebotomy. In cohort 1, 256 participants received vaccine (3 × 103 n=64, 3 × 104 n=64, 3 × 105 n=64, or 3 × 106 PFU n=64) and 74 received placebo. In cohort 2, 162 participants received vaccine (3 × 106 n=20, 9 × 106 n=47, 2 × 107 n=47, or 1 × 108 PFU n=48) and 20 received placebo. Most adverse events occurred in the first day after vaccination, and were mild to moderate in intensity, of a short duration, and more frequent at high vaccine doses (9 × 106 PFU and greater). At the 2 × 107 PFU dose (used in phase 3 trials), the most common local adverse events versus placebo within the first 14 days were arm pain (57·4% 27 of 47 vs 7·4% seven of 94) and local tenderness (59·6% 28 of 47 vs 8·5% eight of 94). The most common systemic adverse events at the 2 × 107 PFU dose versus placebo, occurring in the first 14 days, were headache (46·8% 22 of 47 vs 27·7% 26 of 94), fatigue (38·3% 18 of 47 vs 19·1% 18 of 94), myalgia (34·0% 16 of 47 vs 10·6% 10 of 94), subjective fever (29·8% 14 of 47 vs 2·1% two of 94), shivering or chills (27·7% 13 of 47 vs 7·4% seven of 94), sweats (23·4% 11 of 47 vs 3·2% three of 94), joint aches and pain (19·1% nine of 47 vs 7·4% seven of 94), objective fever (14·9% seven of 47 vs 1·1% one of 94), and joint tenderness or swelling (14·9% seven of 47 vs 2·1% two of 94). Self-limited, post-vaccination arthritis occurred in 4·5% (19 of 418) of vaccinees (median onset 12·0 days IQR 10–14; median duration 8·0 days 6–15) versus 3·2% (three of 94) of controls (median onset 15·0 days 6–20; median duration 47·0 days 37–339), with no apparent dose relationship. Post-vaccination dermatitis occurred in 5·7% (24 of 418) of vaccinees (median onset 9·0 days IQR 2–12; median duration 7·0 days 4–9) versus 3·2% (three of 94) of controls (median onset 5·0 days 3–53; median duration 33·0 days 5–370). A low-level, transient, dose-dependent viraemia occurred in concert with early reactogenicity. Antibody responses were observed in most participants by day 14. IgG and neutralising antibody titres were dose-related (p=0·0003 for IgG ELISA and p<0·0001 for the 60% plaque-reduction neutralisation test PRNT60 by linear trend). On day 28 at the 2 × 107 PFU dose, the geometric mean IgG ELISA endpoint titre was 1624 (95% CI 1146–2302) and seroconversion was 95·7% (95% CI 85·5–98·8); the geometric mean neutralising antibody titre by PRNT60 was 250 (176–355) and seroconversion was 95·7% (85·5–98·8). These robust immunological responses were sustained for 1 year. Interpretation rVSV∆G-ZEBOV-GP was well tolerated and stimulated a rapid onset of binding and neutralising antibodies, which were maintained through to day 360. The immunogenicity results support selection of the 2 × 107 PFU dose. Funding Biomedical Advanced Research and Development Authority, US Department of Health and Human Services.
To examine the accuracy of clinical staging and its effects on outcome in bladder cancer (BC) patients treated with radical cystectomy (RC), using a large national database.
A total of 16,953 ...patients with BC without distant metastases treated with RC from 1998 to 2009 were analyzed. Factors associated with clinical-pathologic stage discrepancy were assessed by multivariate generalized estimating equation models. Survival analysis was conducted for patients treated between 1998 and 2004 (n=7270) using the Kaplan-Meier method and Cox proportional hazards models.
At RC 41.9% of patients were upstaged, whereas 5.9% were downstaged. Upstaging was more common in females, the elderly, and in patients who underwent a more extensive lymphadenectomy. Downstaging was less common in patients treated at community centers, in the elderly, and in Hispanics. Receipt of preoperative chemotherapy was highly associated with downstaging. Five-year overall survival rates for patients with clinical stages 0, I, II, III, and IV were 67.2%, 62.9%, 50.4%, 36.9%, and 27.2%, respectively, whereas those for the same pathologic stages were 70.8%, 75.8%, 63.7%, 41.5%, and 24.7%, respectively. On multivariate analysis, upstaging was associated with increased 5-year mortality (hazard ratio HR 1.80, P<.001), but downstaging was not associated with survival (HR 0.88, P=.160). In contrast, more extensive lymphadenectomy was associated with decreased 5-year mortality (HR 0.76 for ≥10 lymph nodes examined, P<.001), as was treatment at an National Cancer Institute-designated cancer center (HR 0.90, P=.042).
Clinical-pathologic stage discrepancy in BC patients is remarkably common across the United States. These findings should be considered when selecting patients for preoperative or nonoperative management strategies and when comparing the outcomes of bladder sparing approaches to RC.
The success of carotid artery stenting in preventing stroke requires a low risk of periprocedural stroke and death. A comprehensive training and credentialing process was prerequisite to the ...randomized Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) to assemble a competent team of interventionalists with low periprocedural event rates. Interventionalists submitted cases to a multidisciplinary Interventional Management Committee. This committee evaluated 427 applicants. Of these, 238 (56%) were selected to participate in the training program and the lead-in phase, 73 (17%) who had clinical registry experience and satisfactory results with the devices used in CREST were exempt from training and were approved for the randomized phase, and 116 (27%) did not qualify for training. At 30 days in the lead-in study, stroke, myocardial infarction, or death occurred in 6.1% of symptomatic subjects and 4.8% of asymptomatic subjects. Stroke or death occurred in 5.8% of symptomatic subjects and 3.8% of asymptomatic subjects. Outcomes were better for younger subjects and varied by operator training. Based on experience, training, and lead-in results, the Interventional Management Committee selected 224 interventionalists to participate in the randomized phase of CREST. We believe that the credentialing and training of interventionalists participating in CREST have been the most rigorous reported to date for any randomized trial evaluating endovascular treatments. The study identified competent operators, which ensured that the randomized trial results fairly contrasted outcomes between endarterectomy and stenting.
The purpose of the present study was to assess clinical outcomes and closure status after the transcatheter closure of patent foramen ovale. Two hundred thirty-seven consecutive patients (mean age 53 ...± 15 years; 48% men) who underwent patent foramen ovale closure for the prevention of recurrent stroke were evaluated. Primary end points were death, recurrent stroke, and residual right-to-left shunt (RLS). Closure status was monitored at 1, 6, 12, 24, 36, and 48 months after the index procedure by power M-mode transcranial Doppler and was defined by the number of embolic tracks detected after the release of a sustained, calibrated Valsalva maneuver. During a mean follow-up period of 568 ± 364 days, the cumulative event rate for recurrent stroke (n = 8) was 3.4%, for an estimated event-free survival of 0.94 (SE 0.03). There was a significant difference in the estimated probability of recurrent stroke for patients grouped by age (≤55 years 1.4% vs >55 years 6.6%, p = 0.03). There were 7 deaths (3.0%), 1 secondary to and 6 unrelated to recurrent strokes, and 3 surgical explantations (1.3%). Event-free survival, defined as freedom from death, stroke, or explantation, was 0.92 (SE 0.02). The magnitude of RLS was significantly less at late follow-up compared with baseline (grade 4.6 ± 0.7 vs 1.8 ± 1.6, p <0.001). Complete closure or minimal residual RLS (grade 0 to II) was achieved in 66% of patients. Device type (CardioSEAL or Amplatzer) did not affect the risk for adverse events or the presence of large residual RLS. In conclusion, transcatheter patent foramen ovale closure is associated with a low recurrent stroke rate in long-term follow-up.
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