Surgery or Endovascular Therapy for Chronic Limb-Threatening Ischemia.

BACKGROUND: Patients with chronic limb-threatening ischemia (CLTI) require revascularization to improve limb perfusion and thereby limit the risk of amputation. It is uncertain whether an initial strategy of endovascular therapy or surgical revascularization for CLTI is superior for improving limb outcomes. METHODS: In this international, randomized trial, we enrolled 1830 patients with CLTI and infrainguinal peripheral artery disease in two parallel-cohort trials. Patients who had a single segment of great saphenous vein that could be used for surgery were assigned to cohort 1. Patients who needed an alternative bypass conduit were assigned to cohort 2. The primary outcome was a composite of a major adverse limb event - which was defined as amputation above the ankle or a major limb reintervention (a new bypass graft or graft revision, thrombectomy, or thrombolysis) - or death from any cause. RESULTS: In cohort 1, after a median follow-up of 2.7 years, a primary-outcome event occurred in 302 of 709 patients (42.6%) in the surgical group and in 408 of 711 patients (57.4%) in the endovascular group (hazard ratio, 0.68; 95% confidence interval [CI], 0.59 to 0.79; P<0.001). In cohort 2, a primary-outcome event occurred in 83 of 194 patients (42.8%) in the surgical group and in 95 of 199 patients (47.7%) in the endovascular group (hazard ratio, 0.79; 95% CI, 0.58 to 1.06; P = 0.12) after a median follow-up of 1.6 years. The incidence of adverse events was similar in the two groups in the two cohorts. CONCLUSIONS: Among patients with CLTI who had an adequate great saphenous vein for surgical revascularization (cohort 1), the incidence of a major adverse limb event or death was significantly lower in the surgical group than in the endovascular group. Among the patients who lacked an adequate saphenous vein conduit (cohort 2), the outcomes in the two groups were similar. (Funded by the National Heart, Lung, and Blood Institute; BEST-CLI ClinicalTrials.gov number, NCT02060630.).

Real-World Safety Analysis of Paclitaxel Devices Used for the Treatment of Peripheral Artery Disease.

PURPOSE: To investigate the real-world safety of paclitaxel (PTX)-coated devices for treating lower extremity peripheral artery disease using a commercial claims database. MATERIALS AND METHODS: Data from FAIR Health, the largest commercial claims data warehouse in the United States, were used for this study. The study consisted of patients who underwent femoropopliteal revascularization procedures between January 1, 2015, and December 31, 2019, with PTX and non-PTX devices. The primary outcome was 4-year survival following treatment. The secondary outcomes included 2-year survival, 2- and 4-year freedom from amputation, and repeat revascularization. Propensity score matching was used to minimize confounding, and the Kaplan-Meier methods were used to estimate survival. RESULTS: A total of 10,832 procedures were included in the analysis, including 4,962 involving PTX devices and 5,870 involving non-PTX devices. PTX devices were associated with a reduced hazard of death following treatment at 2 and 4 years (hazard ratio [HR], 0.74 [95% confidence interval {CI}, 0.69-0.79]; P <.05, and HR, 0.89 [95% CI, 0.77-1.02]; log-rank P =.018, respectively). The risk of amputation was also lower following treatment with PTX devices than with non-PTX devices at 2 and 4 years (HR, 0.82 [95% CI, 0.76-0.87]; P =.02, and HR, 0.77 [95% CI, 0.67-0.89]; log-rank P =.01, respectively). In addition, the odds of repeat revascularization were similar with PTX and non-PTX devices at 2 and 4 years. CONCLUSIONS: In the real-world commercial claims database, no short- or long-term signal for increased mortality or amputations was observed following treatment with PTX devices.

Enrollment Obstacles in a Randomized Controlled Trial: A Performance Survey of Enrollment in BEST-CLI Sites.

BACKGROUND: Although randomized controlled trials (RCTs) provide the most reliable form of scientific evidence, they are challenging to complete because of a variety of enrollment obstacles. We evaluated obstacles in a large RCT by comparing survey results at high-performing sites (HPS) and low-performing sites (LPS). METHODS: The Best Endovascular versus Best Surgical Therapy in Patients with Critical Limb Ischemia (BEST-CLI) trial is a prospective, pragmatic, multicenter, and multispecialty RCT that will compare clinical outcomes, quality of life, and cost in patients with CLI randomized to surgical bypass or endovascular therapy. BEST-CLI aims to enroll 2100 patients at 160 sites in North America, Europe, and New Zealand. We surveyed the 30 HPS and 30 LPS to assess perceptions of enrollment obstacles. HPS were defined by enrollment of 0.5 subjects or more per month or more than 8 total subjects enrolled. LPS were defined by enrollment of 0.1 subjects per month or only 1 subject total. Responses were compared by site performance status. RESULTS: There were 22 of 30 (73%) HPS and 14 of 30 (47%) LPS that answered the survey (P = 0.06), including 17 investigators and 31 coordinators. The mean total enrollment and rate of enrollment at HPS and LPS were 12.5 subjects at 1.5 subjects/month and 1.0 subject at 0.1 subjects/month, respectively. The most common barrier to enrollment at HPS was difficulty convincing patients and their families to participate (36%), whereas at LPS both difficulty convincing patients and difficulty motivating investigators to enroll (29% each) were most frequently cited. At HPS, the most common obstacle to consenting patients for the trial was patient/family having strong preference toward revascularization strategy (32%) and at LPS it was patient/family not wanting to have treatment chosen at random (36%). At 55% of HPS and 43% of LPS, the trial team was reported as extremely collaborative (P = 0.73), whereas 68% of HPS and 64% of LPS reported having identified a trial champion on their team (P = 1). The most restrictive perceived enrollment criterion at HPS was prior index limb stenting with significant restenosis (32%), whereas at LPS it was excessive risk for surgical bypass (43%). Materials to aid enrollment were used equally at HPS and LPS: patient brochures at 59% HPS and 64% LPS (P = 1); investigator talking points at 45% of HPS and 36% of LPS (P = 0.73). CONCLUSIONS: Patient perceptions and investigator biases are significant challenges to enrollment in large RCTs. In the BEST-CLI trial, difficulty convincing patients and families to allow treatment randomization and difficulty in motivating investigators were major enrollment obstacles.

Closing in on the PumpKIN Trial of the Jarvik 2015 Ventricular Assist Device.

The Infant Jarvik ventricular assist device (VAD; Jarvik Heart, Inc., New York, NY) has been developed to support the circulation of infants and children with advanced heart failure. The first version of the device was determined to have elevated hemolysis under certain conditions. The objective of this work was to determine appropriate modifications to the Infant Jarvik VAD that would result in acceptably low hemolysis levels. In vitro hemolysis testing revealed that hemolysis was related to the shape of the pump blade tips and a critical speed over which hemolysis would occur. Various design modifications were tested and a final design was selected that met the hemolysis performance goal. The new version was named the Jarvik 2015 VAD. Chronic in vivo tests, virtual fit studies, and a series of other performance tests were carried out to assess the device's performance characteristics. In vivo test results revealed acceptable hemolysis levels in a series of animals and virtual fit studies showed that the device would fit into children 8 kg and above, but could fit in smaller children as well. Additional FDA-required testing has been completed and all of the data are being submitted to the FDA so that a clinical trial of the Jarvik 2015 VAD can begin. Development of a Jarvik VAD for use in young children has been challenging for various reasons. However, with the hemolysis issue addressed in the Jarvik 2015 VAD, the device is well-poised for the start of the PumpKIN clinical trial in the near future.

Testosterone treatment is not associated with increased risk of adverse cardiovascular events: results from the Registry of Hypogonadism in Men (RHYME).

AIMS: The aim of this study was to assess cardiovascular (CV) safety of testosterone replacement therapy (TRT) in a large, diverse cohort of European men with hypogonadism (HG). METHODS: The Registry of Hypogonadism in Men (RHYME) was designed as a multi-national, longitudinal disease registry of men diagnosed with hypogonadism (HG) at 25 clinical sites in six European countries. Data collection included a complete medical history, physical examination, blood sampling and patient questionnaires at multiple study visits over 2-3 years. Independent adjudication was performed on all mortalities and CV outcomes. RESULTS: Of 999 patients enrolled with clinically diagnosed HG, 750 (75%) initiated some form of TRT. Registry participants, including both treated and untreated patients, contributed 23 900 person-months (99.6% of the targeted) follow-up time. A total of 55 reported CV events occurred in 41 patients. Overall, five patients died of CV-related causes (3 on TRT, 2 untreated) and none of the deaths were adjudicated as treatment-related. The overall CV incidence rate was 1522 per 100 000 person-years. CV event rates for men receiving TRT were not statistically different from untreated men (P=.70). Regardless of treatment assignment, CV event rates were higher in older men and in those with increased CV risk factors or a prior history of CV events. CONCLUSIONS: Age and prior CV history, not TRT use, were predictors of new-onset CV events in this multi-national, prospective hypogonadism registry.

Strategies for multivessel revascularization in patients with diabetes.

BACKGROUND: In some randomized trials comparing revascularization strategies for patients with diabetes, coronary-artery bypass grafting (CABG) has had a better outcome than percutaneous coronary intervention (PCI). We sought to discover whether aggressive medical therapy and the use of drug-eluting stents could alter the revascularization approach for patients with diabetes and multivessel coronary artery disease. METHODS: In this randomized trial, we assigned patients with diabetes and multivessel coronary artery disease to undergo either PCI with drug-eluting stents or CABG. The patients were followed for a minimum of 2 years (median among survivors, 3.8 years). All patients were prescribed currently recommended medical therapies for the control of low-density lipoprotein cholesterol, systolic blood pressure, and glycated hemoglobin. The primary outcome measure was a composite of death from any cause, nonfatal myocardial infarction, or nonfatal stroke. RESULTS: From 2005 through 2010, we enrolled 1900 patients at 140 international centers. The patients' mean age was 63.1±9.1 years, 29% were women, and 83% had three-vessel disease. The primary outcome occurred more frequently in the PCI group (P=0.005), with 5-year rates of 26.6% in the PCI group and 18.7% in the CABG group. The benefit of CABG was driven by differences in rates of both myocardial infarction (P<0.001) and death from any cause (P=0.049). Stroke was more frequent in the CABG group, with 5-year rates of 2.4% in the PCI group and 5.2% in the CABG group (P=0.03). CONCLUSIONS: For patients with diabetes and advanced coronary artery disease, CABG was superior to PCI in that it significantly reduced rates of death and myocardial infarction, with a higher rate of stroke. (Funded by the National Heart, Lung, and Blood Institute and others; FREEDOM ClinicalTrials.gov number, NCT00086450.).

Contemporary results of carotid endarterectomy in "normal-risk" patients from the Society for Vascular Surgery Vascular Registry.

OBJECTIVE: Acceptable complication rates after carotid endarterectomy (CEA) are drawn from decades-old data. The recent Carotid Revascularization Endarterectomy versus Stenting Trial (CREST) demonstrated improved stroke and mortality outcomes after CEA compared with carotid artery stenting, with 30-day periprocedural CEA stroke rates of 3.2% and 1.4% for symptomatic (SX) and asymptomatic (ASX) patients, respectively. It is unclear whether these target rates can be attained in "normal-risk" (NR) patients experienced outside of the trial. This study was done to determine the contemporary results of CEA from a broader selection of NR patients. METHODS: The Society for Vascular Surgery (SVS) Vascular Registry was examined to determine in-hospital and 30-day event rates for NR, SX, and ASX patients undergoing CEA. NR was defined as patients without anatomic or physiologic risk factors as defined by SVS Carotid Practice Guidelines. Raw data and risk-adjusted rates of death, stroke, and myocardial infarction (MI) were compared between the ASX and SX cohorts. RESULTS: There were 3977 patients (1456 SX, 2521 ASX) available for comparison. The SX group consisted of more men (61.7% vs 57.0%; P = .0045) but reflected a lower proportion of white patients (91.3% vs 94.4%; P = .0002), with lower prevalence of coronary artery disease (P < .0001), prior MI (P < .0001), peripheral vascular disease (P = .0017), and hypertension (P = .029), although New York Heart Association grade >3 congestive heart failure was equally present in both groups (P = .30). Baseline stenosis >80% on duplex imaging was less prevalent among SX patients (54.2% vs 67.8%; P < .0001). Perioperative stroke rates were higher for SX patients in the hospital (2.8% vs 0.8%; P < .0001) and at 30 days (3.4% vs 1.0%; P < .0001), which contributed to the higher composite death, stroke, and MI rates in the hospital (3.6% vs 1.8; P = .0003) and at 30 days (4.5% vs 2.2%; P < .0001) observed in SX patients. After risk adjustment, the rate of stroke/death was greater among SX patients in the hospital (odds ratio, 2.05; 95% confidence interval, 1.18-3.58) although not at 30 days (odds ratio, 1.36; 95% confidence interval, 0.85-2.17). No in-hospital or 30-day differences were observed for death or MI by symptom status. CONCLUSIONS: The SVS Vascular Registry results for CEA in NR patients are similar by symptom status to those reported for CREST and may serve as a benchmark for comparing results of alternative therapies for treatment of carotid stenosis in NR patients outside of monitored clinical trials. The contemporary perioperative risk of stroke after CEA in NR patients continues to be higher for SX than for ASX patients.

The influence of contralateral occlusion on results of carotid interventions from the Society for Vascular Surgery Vascular Registry.

OBJECTIVE: Data on the influence of contralateral carotid occlusion (CCO) on carotid endarterectomy (CEA) are conflicting and are absent for carotid artery stenting (CAS). This study evaluated the influence of CCO on CEA and CAS. METHODS: We evaluated patients with and without CCO in the Society for Vascular Surgery Vascular Registry. Primary outcome was a composite of periprocedural death, stroke, or myocardial infarction (MI) (major adverse cardiovascular events [MACE]) and its individual components. Further analysis was done to identify the influence, if any, of symptom status on outcomes. RESULTS: There were 1128 CAS and 666 CEA patients with CCO. CAS patients were more often symptomatic with a greater incidence of coronary artery disease, congestive heart failure, diabetes, chronic obstructive pulmonary disease, and New York Heart Association class >III. Absolute risk of periprocedural MACE (2.7% for CAS vs. 4.2% for CEA), death (1.1% for CAS vs. 0.7% for CEA), stroke (2.1% for CAS vs. 3.1% for CEA), and MI (0.3% for CAS vs. 0.6% for CEA) was statistically equivalent for both. This equivalence was maintained when patients with CCO were segregated according to symptom status and after adjusting for periprocedural risk. There were 16,646 patients without contralateral occlusion (5698 CAS; 10,948 CEA). Patients without contralateral occlusion with CEA have better outcomes in periprocedural MACE (1.8% for patients without contralateral occlusion vs 4.2% for patients with CCO), and stroke (1.1% for patients without contralateral occlusion vs. 3.1% for patients with CCO) (P < .0001 for both). In CAS patients, CCO did not significantly affect periprocedural MACE (3.2% for patients without contralateral occlusion vs. 2.7% for patients with CCO), death (0.8% for patients without contralateral occlusion vs. 1.0% for patients with CCO), stroke (2.3% for patients without contralateral occlusion vs. 2.1% for patients with CCO), or MI (0.6% for patients without contralateral occlusion vs. 0.3% for patients with CCO). In CEA patients, CCO increased MACE, primarily by increasing stroke rates in asymptomatic (0.7% vs. 2.0%; P = .0095) and symptomatic (1.7% vs. 4.9%; P = .0012) patients. CONCLUSIONS: Although CEA is preferred in patients without contralateral occlusion, regardless of symptom status, based on lower rates of periprocedural MACE, death, and stroke, the benefit of CEA is lost in patients with CCO because of increased stroke rates in CCO patients after CEA but not after CAS regardless of symptom status. The results of CAS and CEA in patients with CCO are equivalent and within acceptable American Heart Association guidelines.

Gender-specific 30-day outcomes after carotid endarterectomy and carotid artery stenting in the Society for Vascular Surgery Vascular Registry.

OBJECTIVE: Although the optimal treatment of carotid stenosis remains unclear, available data suggest that women have higher risk of adverse events after carotid revascularization. We used data from the Society for Vascular Surgery Vascular Registry to determine the effect of gender on outcomes after carotid endarterectomy (CEA) and carotid artery stenting (CAS). METHODS: There were 9865 patients (40.6% women) who underwent CEA (n = 6492) and CAS (n = 3373). The primary end point was a composite of death, stroke, and myocardial infarction at 30 days. RESULTS: There was no difference in age and ethnicity between genders, but men were more likely to be symptomatic (41.6% vs 38.6%; P < .003). There was a higher prevalence of hypertension and chronic obstructive pulmonary disease in women, whereas men had a higher prevalence of coronary artery disease, history of myocardial infarction, and smoking history. For disease etiology in CAS, restenosis was more common in women (28.7% vs 19.7%; P < .0001), and radiation was higher in men (6.2% vs 2.6%; P < .0001). Comparing by gender, there were no statistically significant differences in the primary end point for CEA (women, 4.07%; men, 4.06%) or CAS (women, 6.69%; men, 6.80%). There remains no difference after stratification by symptomatology and multivariate risk adjustment. CONCLUSIONS: In this large, real-world analysis, women and men demonstrated similar results after CEA or CAS. These data suggest that, contrary to previous reports, women do not have a higher risk of adverse events after carotid revascularization.

Preoperative symptom type influences the 30-day perioperative outcomes of carotid endarterectomy and carotid stenting in the Society for Vascular Surgery Vascular Registry.

OBJECTIVE: The objective of this study was to determine the effect of presenting symptom types on 30-day periprocedural outcomes of carotid endarterectomy (CEA) and carotid artery stenting (CAS) in contemporary vascular practice. METHODS: Retrospective review was undertaken of the Society for Vascular Surgery Vascular Registry database subjects who underwent CEA or CAS from 2004 to 2011. Patients were grouped by discrete 12-month preprocedural ipsilateral symptom type: stroke, transient ischemic attack (TIA), transient monocular blindness (TMB), or asymptomatic (ASX). Risk-adjusted odds ratios (ORs) were used to compare the likelihood of the 30-day outcomes of death, stroke, and myocardial infarction (MI) and the composite outcomes of death + stroke and death + stroke + MI. RESULTS: Symptom type significantly influences risk-adjusted 30-day outcomes for carotid intervention. Presentation with stroke predicted the poorest outcomes (death + stroke + MI composite: OR, 1.3; 95% confidence interval [CI], 0.83-2.03 vs TIA; OR, 2.56; 95% CI, 1.18-5.57 vs TMB; OR, 2.12; 95% CI, 1.46-3.08 vs ASX), followed by TIA (death + stroke + MI composite: OR, 1.97; 95% CI, 0.91-4.25 vs TMB; OR, 1.63; 95% CI, 1.14-2.33 vs ASX). For both CAS and CEA patients, presentation with stroke or TIA predicted a higher risk of periprocedural stroke than in ASX patients. Presentation with stroke predicted higher 30-day risk of death with CAS but not with CEA. MI rates were not affected by presenting symptom type. The 30-day outcomes for the TMB and ASX patient groups were equivalent in both treatment arms. CONCLUSIONS: Presenting symptom type significantly affects the 30-day outcomes of both CAS and CEA in contemporary vascular surgical practice. Presentation with stroke and TIA predicts higher rates of periprocedural complications, whereas TMB presentation predicts a periprocedural risk profile similar to that of ASX disease.

The impact of Centers for Medicare and Medicaid Services high-risk criteria on outcome after carotid endarterectomy and carotid artery stenting in the SVS Vascular Registry.

OBJECTIVE: The Centers for Medicare and Medicaid Services (CMS) require high-risk (HR) criteria for carotid artery stenting (CAS) reimbursement. The impact of these criteria on outcomes after carotid endarterectomy (CEA) and CAS remains uncertain. Additionally, if these HR criteria are associated with more adverse events after CAS, then existing comparative effectiveness analysis of CEA vs CAS may be biased. We sought to elucidate this using data from the SVS Vascular Registry. METHODS: We analyzed 10,107 patients undergoing CEA (6370) and CAS (3737), stratified by CMS HR criteria. The primary endpoint was composite death, stroke, and myocardial infarction (MI) (major adverse cardiovascular event [MACE]) at 30 days. We compared baseline characteristics and outcomes using univariate and multivariable analyses. RESULTS: CAS patients were more likely to have preoperative stroke (26% vs 21%) or transient ischemic attack (23% vs 19%) than CEA. Although age ≥ 80 years was similar, CAS patients were more likely to have all other HR criteria. For CEA, HR patients had higher MACEs than normal risk in both symptomatic (7.3% vs 4.6%; P < .01) and asymptomatic patients (5% vs 2.2%; P < .0001). For CAS, HR status was not associated with a significant increase in MACE for symptomatic (9.1% vs 6.2%; P = .24) or asymptomatic patients (5.4% vs 4.2%; P = .61). All CAS patients had MACE rates similar to HR CEA. After multivariable risk adjustment, CAS had higher rates than CEA for MACE (odds ratio [OR], 1.2; 95% confidence interval [CI], 1.0-1.5), death (OR, 1.5; 95% CI, 1.0-2.2), and stroke (OR, 1.3; 95% CI,1.0-1.7), whereas there was no difference in MI (OR, 0.8; 95% CI, 0.6-1.3). Among CEA patients, age ≥ 80 (OR, 1.4; 95% CI, 1.02-1.8), congestive heart failure (OR, 1.7; 95% CI, 1.03-2.8), EF <30% (OR, 3.5; 95% CI, 1.6-7.7), angina (OR, 3.9; 95% CI, 1.6-9.9), contralateral occlusion (OR, 3.2; 95% CI, 2.1-4.7), and high anatomic lesion (OR, 2.7; 95% CI, 1.33-5.6) predicted MACE. Among CAS patients, recent MI (OR, 3.2; 95% CI, 1.5-7.0) was predictive, and radiation (OR, 0.6; 95% CI, 0.4-0.8) and restenosis (OR, 0.5; 95% CI, 0.3-0.96) were protective for MACE. CONCLUSIONS: Although CMS HR criteria can successfully discriminate a group of patients at HR for adverse events after CEA, certain CMS HR criteria are more important than others. However, CEA appears safer for the majority of patients with carotid disease. Among patients undergoing CAS, non-HR status may be limited to restenosis and radiation.

Registry of Hypogonadism in Men (RHYME): design of a multi-national longitudinal, observational registry of exogenous testosterone use in hypogonadal men.

OBJECTIVE: Despite the prevalence of hypogonadism (HG) and widespread use of testosterone therapy, little is known about the safety/effectiveness of long-term testosterone use. The Registry of Hypogonadism in Men (RHYME) is a multi-national patient registry assessing prostate health and other outcomes associated with testosterone treatment in men. DESIGN: Observational patient disease registry. METHODS: RHYME is a non-interventional disease registry with longitudinal data collection on a large sample (N = 999) of well-characterized, hypogonadal men aged 18 years or older. The Registry will prospectively evaluate male patients diagnosed with HG, who have not previously been treated with testosterone therapy. Key design features include: (1) broad inclusion/exclusion criteria, (2) standardized central laboratory hormone assays, (3) independent adjudication of prostate biopsies and mortalities, (4) standard of care treatment, (5) comprehensive medical record and questionnaire data at six months and annually post-enrollment and (6) adequate statistical power for assessing prostate endpoints at 36 months. RESULTS: A total of 25 clinical sites in six European countries (Germany, Italy, the Netherlands, Spain, Sweden and the United Kingdom) have completed recruitment for the study. Recruitment was initiated in May 2009, and completed in December 2011. Data collection is ongoing with a minimum of two years of follow-up on all patients.

Society for Vascular Surgery (SVS) Vascular Registry evaluation of comparative effectiveness of carotid revascularization procedures stratified by Medicare age.

OBJECTIVE: Recent randomized controlled trials have shown that age significantly affects the outcome of carotid revascularization procedures. This study used data from the Society for Vascular Surgery Vascular Registry (VR) to report the influence of age on the comparative effectiveness of carotid endarterectomy (CEA) and carotid artery stenting (CAS). METHODS: VR collects provider-reported data on patients using a Web-based database. Patients were stratified by age and symptoms. The primary end point was the composite outcome of death, stroke, or myocardial infarction (MI) at 30 days. RESULTS: As of December 7, 2010, there were 1347 CEA and 861 CAS patients aged < 65 years and 4169 CEA and 2536 CAS patients aged ≥ 65 years. CAS patients in both age groups were more likely to have a disease etiology of radiation or restenosis, be symptomatic, and have more cardiac comorbidities. In patients aged <65 years, the primary end point (5.23% CAS vs 3.56% CEA; P = .065) did not reach statistical significance. Subgroup analyses showed that CAS had a higher combined death/stroke/MI rate (4.44% vs 2.10%; P < .031) in asymptomatic patients but there was no difference in the symptomatic (6.00% vs 5.47%; P = .79) group. In patients aged ≥ 65 years, CEA had lower rates of death (0.91% vs 1.97%; P < .01), stroke (2.52% vs 4.89%; P < .01), and composite death/stroke/MI (4.27% vs 7.14%; P < .01). CEA in patients aged ≥ 65 years was associated with lower rates of the primary end point in symptomatic (5.27% vs 9.52%; P < .01) and asymptomatic (3.31% vs 5.27%; P < .01) subgroups. After risk adjustment, CAS patients aged ≥ 65 years were more likely to reach the primary end point. CONCLUSIONS: Compared with CEA, CAS resulted in inferior 30-day outcomes in symptomatic and asymptomatic patients aged ≥ 65 years. These findings do not support the widespread use of CAS in patients aged ≥ 65 years.

The Current Landscape and Emerging Applications for Real-World Data in Diagnostics and Clinical Decision Support and its Impact on Regulatory Decision Making.

Real-world data (RWD) and real-world evidence (RWE) are becoming essential tools for informing regulatory decision making in health care and offer an opportunity for all stakeholders in the healthcare ecosystem to evaluate medical products throughout their lifecycle. Although considerable interest has been given to regulatory decisions supported by RWE for treatment authorization, especially in rare diseases, less attention has been given to RWD/RWE related to in vitro diagnostic (IVD) products and clinical decision support systems (CDSS). This review examines current regulatory practices in relation to IVD product development and discusses the use of CDSS in assisting clinicians to retrieve, filter, and analyze patient data in support of complex decisions regarding diagnosis and treatment. The review then explores how utilizing RWD could augment regulatory body understanding of test performance, clinical outcomes, and benefit-risk profiles, and how RWD could be leveraged to augment CDSS and improve safety, quality, and efficiency of healthcare practices. Whereas we present examples of RWD assisting in the regulation of IVDs and CDSS, we also highlight key challenges within the current healthcare system which are impeding the potential of RWE to be fully realized. These challenges include issues such as data availability, reliability, accessibility, harmonization, and interoperability, often for reasons specific to diagnostics. Finally, we review ways that these challenges are actively being addressed and discuss how private-public collaborations and the implementation of standardized language and protocols are working toward producing more robust RWD and RWE to support regulatory decision making.

Society for Vascular Surgery Vascular Registry evaluation of stent cell design on carotid artery stenting outcomes.

OBJECTIVE: The Society for Vascular Surgery (SVS) Vascular Registry (VR) collects data on outcomes of carotid endarterectomy and carotid artery stenting (CAS). The purpose of this study was to evaluate the impact of open vs closed cell stent design on the in-hospital and 30-day outcome of CAS. METHODS: The VR collects provider-reported data on patients using a Web-based database. Data were analyzed both in-hospital and at 30 days postprocedure. The primary outcome is combined death/stroke/myocardial infarction (MI). RESULTS: As of October 14, 2009, there were 4337 CAS with discharge data and 2397 with 30-day data. Open cell stents (OPEN) were used in 3451 patients (79.6%), and closed cell stents (CLOSED) were used in 866 patients (20.4%). Baseline demographics showed no differences in age, gender, race, and ethnicity. However, the OPEN group had more patients with atherosclerosis (74.5% vs 67.4%; P = .0003) as the etiology of carotid artery disease. The OPEN group also had a higher prevalence of preprocedural stroke (25.8% vs 21.4%; P = .0079), chronic obstructive pulmonary disease (COPD; 21.0% vs 17.6%; P = .0277), cardiac arrhythmia (14.7% vs 11.4%; P = .0108), valvular heart disease (7.4% vs 3.7%; P < .0001), peripheral vascular disease (PVD; 40.0% vs 35.3%; P = .0109), and smoking history (59.0% vs 54.1%; P = .0085). There are no statistically significant differences in the in-hospital or 30-day outcomes between the OPEN and CLOSED patients. Further subgroup analyses demonstrated symptomatic patients had a higher event rate than the asymptomatic cohort in both the OPEN and CLOSED groups. Among symptomatic patients, the OPEN patients had a lower (0.43% vs 1.41%; P = .0349) rate of in-hospital mortality with no difference in stroke or transient ischemic attack (TIA). There were no differences in 30-day event rates. In asymptomatic patients, there were also no statistically significant differences between the OPEN and CLOSED groups. After risk adjustment, there remained no statistically significant differences between groups of the primary endpoint (death/stroke/MI) during in-hospital or 30 days. CONCLUSION: In-hospital and 30-day outcomes after CAS were not significantly influenced by stent cell design. Symptomatic patients had higher adverse event rates compared to the asymptomatic cohort. As there is no current evidence of differential outcome between the use of open and closed cell stents, physicians should continue to use approved stent platforms based on criteria other than stent cell design.

Influence of LDL-Cholesterol Lowering on Cardiovascular Outcomes in Patients With Diabetes Mellitus Undergoing Coronary Revascularization.

BACKGROUND: Elevated low-density lipoprotein cholesterol (LDL-C) is associated with increased cardiovascular events, especially in high-risk populations. OBJECTIVES: This study sought to evaluate the influence of LDL-C on the incidence of cardiovascular events either following a coronary revascularization procedure (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or optimal medical therapy alone in patients with established coronary heart disease and type 2 diabetes (T2DM). METHODS: Patient-level pooled analysis of 3 randomized clinical trials was undertaken. Patients with T2DM were categorized according to the levels of LDL-C at 1 year following randomization. The primary endpoint was major adverse cardiac or cerebrovascular events ([MACCE] the composite of all-cause mortality, nonfatal myocardial infarction, and nonfatal stroke). RESULTS: A total of 4,050 patients were followed for a median of 3.9 years after the index 1-year assessment. Patients whose 1-year LDL-C remained ≥100 mg/dl experienced higher 4-year cumulative risk of MACCE (17.2% vs. 13.3% vs. 13.1% for LDL-C between 70 and <100 mg/dl and LDL-C <70 mg/dl, respectively; p = 0.016). When compared with optimal medical therapy alone, patients with PCI experienced a MACCE reduction only if 1-year LDL-C was <70 mg/dl (hazard ratio: 0.61; 95% confidence interval: 0.40 to 0.91; p = 0.016), whereas CABG was associated with improved outcomes across all 1-year LDL-C strata. In patients with 1-year LDL-C ≥70 mg/dl, patients undergoing CABG had significantly lower MACCE rates as compared with PCI. CONCLUSIONS: In patients with coronary heart disease with T2DM, lower LDL-C at 1 year is associated with improved long-term MACCE outcome in those eligible for either PCI or CABG. When compared with optimal medical therapy alone, PCI was associated with MACCE reductions only in those who achieved an LDL-C <70 mg/dl.

Risk-adjusted 30-day outcomes of carotid stenting and endarterectomy: results from the SVS Vascular Registry.

OBJECTIVE: As the first operational societal registry of carotid procedures, the Outcomes Committee of the Society for Vascular Surgery (SVS) developed the Vascular Registry (VR) in response to the Centers for Medicare and Medicaid Services' (CMS) National Coverage Decision on carotid artery stenting (CAS). Although CMS requires data submission only on CAS, the VR collects similar data on carotid endarterectomy (CEA) to allow comparison of outcomes, as well as potential for expansion to other procedures. METHODS: SVS-VR on-line provider-reported data include baseline through follow-up visits to better understand long-term risks and benefits associated with CAS and CEA. The primary outcomes are combined death, stroke, and myocardial infarction (MI). An independent data coordinating center maintains the database, which is Health Insurance Portability and Accountability Act (HIPAA)-compliant and auditable. RESULTS: As of December 26, 2007, 6403 procedures with discharge data were entered by 287 providers at 56 centers on 2763 CAS patients (1450 with 30-day outcomes, 52.5%) and 3259 CEA patients (1368 with 30-day outcomes, 42%). Of the total cohort, 98% of CEA and 70.7% of CAS (P < .001) were performed for atherosclerotic disease. Restenosis accounted for 22.3% and post-radiation induced stenosis in 4.5% of CAS patients. Preprocedure lateralizing neurologic symptoms were present in a greater proportion of CAS patients (49.2%) than CEA patients (42.4%, P < .001). CAS patients also had higher preprocedure prevalence of coronary artery disease (CAD), MI, congestive heart failure (CHF), chronic obstructive pulmonary disease (COPD), and cardiac arrhythmia. For CAS, death/stroke/MI at 30 days was 7.13% for symptomatic patients and 4.60% for asymptomatic patients (P = .04). For CEA, death/stroke/MI at 30 days was 3.75% in symptomatic patients and 1.97% in asymptomatic patients (P = .05). After risk-adjustment for age, history of stroke, diabetes, and American Society of Anesthesiologists (ASA) grade (ie, factors found to be significant confounders in outcomes using backwards elimination), logistic regression analysis suggested better outcomes following CEA. There were no statistically significant differences when examining CAS outcomes based on center volume. CAS in atherosclerotic disease had significantly worse outcomes than in nonatherosclerotic stenosis. When CAS and CEA were compared in the treatment of atherosclerotic disease only, the difference in outcomes between the two procedures was more pronounced, with death/stroke/MI 6.42% after CAS vs 2.62% following CEA, P < .0001. CONCLUSION: Following best possible risk adjustment of these unmatched groups, symptomatic and asymptomatic CAS patients had significantly higher 30-day postprocedure incidence of death/stroke/MI when compared with CEA patients. The initial 1.5 years of data collection provide proof of concept that a specialty society based VR can succeed in meeting regulatory and scientific goals. With continued enrollment and follow-up, analysis of SVS-VR will supplement randomized trials by providing real-world comparisons of CAS and CEA with sufficient numbers to serve as an outcome assessment tool of important patient subsets and across the spectrum of peripheral vascular procedures.

Carotid revascularization using endarterectomy or stenting systems (CaRESS): 4-year outcomes.

PURPOSE: To examine the 4-year outcomes from Carotid Revascularization using Endarterectomy or Stenting Systems (CaRESS) in light of the current reimbursement guidelines for carotid artery stenting (CAS) from the Centers for Medicare and Medicaid Services (CMS). METHODS: CaRESS was designed as a prospective, nonrandomized comparative cohort study of a broad-risk population of symptomatic and asymptomatic patients with carotid stenosis. In all, 397 patients (247 men; mean age 71 years, range 43-89) were enrolled and underwent carotid endarterectomy (CEA; n = 254) or protected CAS (n = 143). More than 90% of patients had >75% stenosis; two thirds were asymptomatic. The primary endpoints included (1) all-cause mortality, (2) any stroke, and (3) myocardial infarction (MI), as well as the composite endpoints of (4) death and any nonfatal stroke and (5) death, nonfatal stroke, and MI. The secondary endpoints were restenosis, repeat angiography, and carotid revascularization. All patients were classified with respect to surgical risk, symptom status, and stenosis grade based on criteria published by the CMS. In addition, separate analyses were performed comparing genders and octogenarians to those <80 years old. RESULTS: No significant differences in the primary outcome measures were found between the CEA and CAS groups in the 4-year analysis. The incidences of any stroke at 4 years were 9.6% for CEA and 8.6% for CAS (p = 0.444); when combined with death, the composite death/nonfatal stroke rates were 26.5% for CEA versus 21.8% for CAS (p = 0.361). The composite endpoint of death, nonfatal stroke, and MI at 4 years was 27.0% in CEA versus 21.7% in CAS (p = 0.273) patients. The secondary endpoints of restenosis (p = 0.014) and repeat angiography (p = 0.052) were higher in the CAS arm. There were no differences in any of the subgroups stratified according the CMS guidelines or in the gender comparison. Four-year incidences of death/nonfatal stroke and death/nonfatal stroke/MI were higher in the CEA arm among patients <80 years of age (p = 0.049 and p = 0.030, respectively). There were no significant differences between these incidences in the octogenarian subgroup. CONCLUSION: The risk of death or nonfatal stroke 4 years following CAS with distal protection is equivalent to CEA in a broad category of patients with carotid stenosis. There were no significant differences in stroke or mortality rates between high-risk and non-high-risk patients and no differences in outcomes between symptomatic and asymptomatic patients. After 4 years, CAS had a 2-fold higher restenosis rate compared to CEA. The risk of death/stroke or death/stroke/MI appears to be higher following CEA than CAS among patients <80 years of age, yet there is no statistically significant relationship between death, stroke, or MI among octogenarians.

Long-Term Survival Following Multivessel Revascularization in Patients With Diabetes: The FREEDOM Follow-On Study.

BACKGROUND: The FREEDOM (Future Revascularization Evaluation in Patients with Diabetes Mellitus: Optimal Management of Multivessel Disease) trial demonstrated that for patients with diabetes mellitus (DM) and multivessel coronary disease (MVD), coronary artery bypass grafting (CABG) is superior to percutaneous coronary intervention with drug-eluting stents (PCI-DES) in reducing the rate of major adverse cardiovascular and cerebrovascular events after a median follow-up of 3.8 years. It is not known, however, whether CABG confers a survival benefit after an extended follow-up period. OBJECTIVES: The purpose of this study was to evaluate the long-term survival of DM patients with MVD undergoing coronary revascularization in the FREEDOM trial. METHODS: The FREEDOM trial randomized 1,900 patients with DM and MVD to undergo either PCI with sirolimus-eluting or paclitaxel-eluting stents or CABG on a background of optimal medical therapy. After completion of the trial, enrolling centers and patients were invited to participate in the FREEDOM Follow-On study. Survival was evaluated using Kaplan-Meier analysis, and Cox proportional hazards models were used for subgroup and multivariate analyses. RESULTS: A total of 25 centers (of 140 original centers) agreed to participate in the FREEDOM Follow-On study and contributed a total of 943 patients (49.6% of the original cohort) with a median follow-up of 7.5 years (range 0 to 13.2 years). Of the 1,900 patients, there were 314 deaths during the entire follow-up period (204 deaths in the original trial and 110 deaths in the FREEDOM Follow-On). The all-cause mortality rate was significantly higher in the PCI-DES group than in the CABG group (24.3% [159 deaths] vs. 18.3% [112 deaths]; hazard ratio: 1.36; 95% confidence interval: 1.07 to 1.74; p = 0.01). Of the 943 patients with extended follow-up, the all-cause mortality rate was 23.7% (99 deaths) in the PCI-DES group and 18.7% (72 deaths) in the CABG group (hazard ratio: 1.32; 95% confidence interval: 0.97 to 1.78; p = 0.076). CONCLUSIONS: In patients with DM and MVD, coronary revascularization with CABG leads to lower all-cause mortality than with PCI-DES in long-term follow-up. (Comparison of Two Treatments for Multivessel Coronary Artery Disease in Individuals With Diabetes [FREEDOM]; NCT00086450).

Lifeline registry of endovascular aneurysm repair: open repair surgical controls in clinical trials.

PURPOSE: The improvement of available endovascular aortic aneurysm repair (EVAR) devices is critical for the advancement of patient care in vascular surgery. The goal of this article is to report a highly detailed, closely monitored, audited, pooled multicenter cohort of open surgical abdominal aortic aneurysm (AAA) repairs that has potential for use in future EVAR studies as a control data set. METHODS: Open surgical AAA repair data from four investigational device exemption clinical aortic endograft trials were tested for poolability, merged, and analyzed for the intervals of 0 to 30 days and 31 to 365 days. RESULTS: The data set includes 323 open patients (83% men; mean age, 70 years). Operative mortality at 30 days was 2.8%. The mean age of women was 3 years older than men, and mortality at 30 days for women was 5.7% compared with 2.2% for men (P = .18). Operative mortality for patients with large AAAs (>/=5.5 cm, 3.6%) was not different than for patients with small aneurysms (<5.5 cm, 2.4%, P = .54). All-cause mortality at 1 year was 6.7%, with significant predictors including age, sex, and renal failure. Women had 2.6-fold greater 1-year all-cause mortality rate (13.2%) than men (5.4%, P = .04), but statistical significance was lost after correction for age. Two additional AAA-related deaths occurred between days 31 and 365, resulting in a 1-year AAA-related mortality of 3.5%. CONCLUSION: This data set provides a tightly controlled, thoroughly detailed, and audited experience that has the potential to serve as an open control group for future EVAR trials.