Effect of Rivaroxaban and Aspirin in Patients With Peripheral Artery Disease Undergoing Surgical Revascularization: Insights From the VOYAGER PAD Trial.

BACKGROUND: Patients with peripheral artery disease requiring lower extremity revascularization (LER) are at high risk of adverse limb and cardiovascular events. The VOYAGER PAD trial (Vascular Outcomes Study of ASA [Acetylsalicylic Acid] Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) demonstrated that rivaroxaban significantly reduced this risk. The efficacy and safety of rivaroxaban has not been described in patients who underwent surgical LER. METHODS: The VOYAGER PAD trial randomized patients with peripheral artery disease after surgical and endovascular LER to rivaroxaban 2.5 mg twice daily plus aspirin or matching placebo plus aspirin and followed for a median of 28 months. The primary end point was a composite of acute limb ischemia, major vascular amputation, myocardial infarction, ischemic stroke, or cardiovascular death. The principal safety outcome was Thrombolysis in Myocardial Infarction major bleeding. International Society on Thrombosis and Haemostasis bleeding was a secondary safety outcome. All efficacy and safety outcomes were adjudicated by a blinded independent committee. RESULTS: Of the 6564 randomized, 2185 (33%) underwent surgical LER and 4379 (67%) endovascular. Compared with placebo, rivaroxaban reduced the primary end point consistently regardless of LER method (P-interaction, 0.43). After surgical LER, the primary efficacy outcome occurred in 199 (18.4%) patients in the rivaroxaban group and 242 (22.0%) patients in the placebo group with a cumulative incidence at 3 years of 19.7% and 23.9%, respectively (hazard ratio, 0.81 [95% CI, 0.67-0.98]; P=0.026). In the overall trial, Thrombolysis in Myocardial Infarction major bleeding and International Society on Thrombosis and Haemostasis major bleeding were increased with rivaroxaban. There was no heterogeneity for Thrombolysis in Myocardial Infarction major bleeding (P-interaction, 0.17) or International Society on Thrombosis and Haemostasis major bleeding (P-interaction, 0.73) on the basis of the LER approach. After surgical LER, the principal safety outcome occurred in 11 (1.0%) patients in the rivaroxaban group and 13 (1.2%) patients in the placebo group; 3-year cumulative incidence was 1.3% and 1.4%, respectively (hazard ratio, 0.88 [95% CI, 0.39-1.95]; P=0.75) Among surgical patients, the composite of fatal bleeding or intracranial hemorrhage (P=0.95) and postprocedural bleeding requiring intervention (P=0.93) was not significantly increased. CONCLUSIONS: The efficacy of rivaroxaban is associated with a benefit in patients who underwent surgical LER. Although bleeding was increased with rivaroxaban plus aspirin, the incidence was low, with no significant increase in fatal bleeding, intracranial hemorrhage, or postprocedural bleeds requiring intervention. Registration: URL: http://www.clinicaltrials.gov; Unique Identifier: NCT02504216.

Three- and Two-Dimensional Ultrasound is as Accurate as Computed Tomography in Aortic Sac Assessment after Endovascular Aortic Repair.

BACKGROUND: To compare aortic sac changes after endovascular aneurysm repair (EVAR) assessed by three-dimensional ultrasound (3D-US), two-dimensional ultrasound (2D-US), and traditional computed tomographic angiography (CTA). METHODS: Using volume assessment with three-dimensional CTA (3D-CTA-volume) as the gold standard, this study investigated aortic sac changes at three and 12 months after EVAR with three different ultrasound methods (2D-US anterior-posterior (AP) diameter, 3D-US AP centerline diameter, and 3D-US partial volume), and traditional CT multiplanar outer-to-outer diameter (CT-MPR OTO diameter). From august 1st, 2011 to January 2014, consecutive EVAR patients (n = 113) were available for analysis in two time intervals; 1) between preoperative and three-month follow-up and 2) between three and 12 month follow-up. RESULTS: The risk of missing true aortic sac growth (false negative finding) at three-month postoperative visit using 3D-US partial volume, 3D-US AP centerline diameter, 2D-US AP diameter, and CT-MPR OTO diameter was 19%, 21%, 22%, and 18%, respectively. Corresponding low sensitivities (0% to 21%) and kappa-values (<0.50) in detecting aortic sac changes were found. The risk of missing true growth between three and 12 months were lower (6%, 5%, 6%, and 6%, respectively), and matching sensitivities 33%, 33%, 17%, and 17%, respectively. CONCLUSIONS: All tested methods for aortic sac changes were as good as traditional CT-MPR OTO diameter and corresponded poorly with 3D-CTA-volume at three months postoperative visit but substantially better after 12 months where the residual sac change was more profound.

The Short-term Predictive Value of Vessel Wall Stiffness on Abdominal Aortic Aneurysm Growth.

BACKGROUND: Abdominal aortic aneurysm (AAA) surveillance programs are currently based solely on AAA diameter. The diameter criterion alone, however, seems inadequate as small AAAs comprise 5-10 % of ruptured AAAs as well as some large AAAs never rupture. Aneurysm wall stiffness has been suggested to predict rupture and growth; this study aimed to investigate the prognostic value of AAA vessel wall stiffness for growth on prospectively collected data. METHODS: Analysis was based on data from a randomised, placebo-controlled, multicentre trial investigating mast-cell-inhibitors to halt aneurysm growth (the AORTA trial). Systolic and diastolic AAA diameter was determined in 326 patients using electrocardiogram-gated ultrasound (US). Stiffness was calculated at baseline and after 1 year. RESULTS: Maximum AAA diameter increased from 44.1 mm to 46.5 mm during the study period. Aneurysm growth after 1 year was not predicted by baseline stiffness (-0.003 mm/U; 95 % CI: -0.007 to 0.001 mm/U; P = 0.15). Throughout the study period, stiffness remained unchanged (8.3 U; 95 % CI: -2.5 to 19.1 U; P = 0.13) and without significant correlation to aneurysm growth (R: 0.053; P = 0.38). CONCLUSIONS: Following a rigorous US protocol, this study could not confirm AAA vessel wall stiffness as a predictor of aneurysm growth in a 1-year follow-up design. The need for new and subtle methods to complement diameter for improved AAA risk assessment is warranted.

Cutdown Technique is Superior to Fascial Closure for Femoral Artery Access after Elective Endovascular Aortic Repair.

OBJECTIVES: Arterial access closure after endovascular aneurysm repair (EVAR) can be achieved using three different approaches: percutaneous closure devices, surgical exposure and direct suture ("cutdown"), and the less invasive fascial closure technique. The aim of this study was to report on the intra-operative, in hospital, and three month outcome of fascial closure and cutdown, and to determine risk factors for failure. METHODS: The primary outcome was assessed in 439 groins in 225 elective EVAR patients recruited consecutively and prospectively from February 1, 2011 to August 31, 2014. During the study period, fascial closure and cutdown were first and second line closing techniques. Compared with fascial closure, procedures completed with cutdown had lower BMI, thinner subcutaneous tissue of the groin and more complex femoral anatomy. Computed tomographic angiography (CTA) and duplex ultrasound (DUS) of the groin were performed pre-operatively and three months after EVAR. Retrospective review of medical records and CTA were used to determine intra-operative and in hospital outcome, and risk factors for failure. RESULTS: In total, 64%, 33%, and 3% were completed with fascial closure, cutdown, and closure device, respectively. Intra-operative, in hospital, and three month technical success rates of fascial closure vs. cutdown were 91% (283/310 groins) vs. 99% (114/115 groins), 89% (277/310 groins) vs. 99% (114/115 groins), and 89% (275/310 groins) vs. 99% (114/115 groins) (p < .001). Wound complications within three months were infrequent for both methods. No risk factor was significantly associated with failure after fascial closure. CONCLUSION: This study shows that cutdown is superior to fascial closure for femoral artery access after elective EVAR. In acute EVAR, however, fascial closure is still considered to be a good and fast method, and it has been kept in the present authors' armamentarium for this indication.

Proteomic analysis of the extracellular matrix of human atherosclerotic plaques shows marked changes between plaque types.

Cardiovascular disease is the leading cause of death, with atherosclerosis the major underlying cause. While often asymptomatic for decades, atherosclerotic plaque destabilization and rupture can arise suddenly and cause acute arterial occlusion or peripheral embolization resulting in myocardial infarction, stroke and lower limb ischaemia. As extracellular matrix (ECM) remodelling is associated with plaque instability, we hypothesized that the ECM composition would differ between plaques. We analyzed atherosclerotic plaques obtained from 21 patients who underwent carotid surgery following recent symptomatic carotid artery stenosis. Plaques were solubilized using a new efficient, single-step approach. Solubilized proteins were digested to peptides, and analyzed by liquid chromatography-mass spectrometry using data-independent acquisition. Identification and quantification of 4498 plaque proteins was achieved, including 354 ECM proteins, with unprecedented coverage and high reproducibility. Multidimensional scaling analysis and hierarchical clustering indicate two distinct clusters, which correlate with macroscopic plaque morphology (soft/unstable versus hard/stable), ultrasound classification (echolucent versus echogenic) and the presence of hemorrhage/ulceration. We identified 714 proteins with differential abundances between these groups. Soft/unstable plaques were enriched in proteins involved in inflammation, ECM remodelling, and protein degradation (e.g. matrix metalloproteinases, cathepsins). In contrast, hard/stable plaques contained higher levels of ECM structural proteins (e.g. collagens, versican, nidogens, biglycan, lumican, proteoglycan 4, mineralization proteins). These data indicate that a single-step proteomics method can provide unique mechanistic insights into ECM remodelling and inflammatory mechanisms within plaques that correlate with clinical parameters, and help rationalize plaque destabilization. These data also provide an approach towards identifying biomarkers for individualized risk profiling of atherosclerosis.

One-year volume growth of abdominal aortic aneurysms measured by extended field-of-view ultrasound.

BACKGROUND: Measurement of volume has the potential to detect subtle growth not recognized in the current surveillance paradigm of abdominal aortic aneurysms (AAAs). Currently available three-dimensional ultrasound allows for estimation of AAA volume, but for most patients, the AAA extends beyond the ultrasound field-of-view and only allows visualization of a partial AAA volume. A new extended field-of-view three-dimensional ultrasound protocol (XFoV US) has been found to improve the proportion of patients with visualization of the full AAA volume. METHODS: To investigate the applicability of the XFoV US protocol in estimating AAA volume growth in follow-up, 86 patients with AAAs were recruited from the surveillance program at a university hospital. All were imaged by XFoV US at baseline and at one-year follow-up. RESULTS: Assessment of full volume, based on visualization of the AAA neck and bifurcation at both baseline and one-year follow-up, was achieved in 67/86 (78%) of patients. One-year mean growth in maximum diameter was 2.8 mm (6%/year), in centerline length 2.9 mm (4%/year), and in volume 15.9 mL (19%/year). In 17/67 (25%) of patients, volume growth was detected in diameter-stable AAAs. Baseline XFoV US volume was associated with one-year AAA volume growth, while, conversely, maximum baseline diameter was not associated with one-year AAA diameter growth. CONCLUSIONS: This study concludes that the XFoV US protocol provides a safe and repeatable modality for assessing AAA volume growth, and that AAA volume is a promising predictive measure of AAA growth.

Precision medicine for cardiometabolic disease: a framework for clinical translation.

Cardiometabolic disease is a major threat to global health. Precision medicine has great potential to help to reduce the burden of this common and complex disease cluster, and to enhance contemporary evidence-based medicine. Its key pillars are diagnostics; prediction (of the primary disease); prevention (of the primary disease); prognosis (prediction of complications of the primary disease); treatment (of the primary disease or its complications); and monitoring (of risk exposure, treatment response, and disease progression or remission). To contextualise precision medicine in both research and clinical settings, and to encourage the successful translation of discovery science into clinical practice, in this Series paper we outline a model (the EPPOS model) that builds on contemporary evidence-based approaches; includes precision medicine that improves disease-related predictions by stratifying a cohort into subgroups of similar characteristics, or using participants' characteristics to model treatment outcomes directly; includes personalised medicine with the use of a person's data to objectively gauge the efficacy, safety, and tolerability of therapeutics; and subjectively tailors medical decisions to the individual's preferences, circumstances, and capabilities. Precision medicine requires a well functioning system comprised of multiple stakeholders, including health-care recipients, health-care providers, scientists, health economists, funders, innovators of medicines and technologies, regulators, and policy makers. Powerful computing infrastructures supporting appropriate analysis of large-scale, well curated, and accessible health databases that contain high-quality, multidimensional, time-series data will be required; so too will prospective cohort studies in diverse populations designed to generate novel hypotheses, and clinical trials designed to test them. Here, we carefully consider these topics and describe a framework for the integration of precision medicine in cardiometabolic disease.

Inter-Scan Reproducibility of Carotid Plaque Volume Measurements by 3-D Ultrasound.

We tested a novel 3-D matrix transducer with respect to inter-scan reproducibility of carotid maximum plaque thickness (MPT) and volume measurements. To improve reproducibility while focusing on the largest plaque/most diseased part of the carotid artery, we introduced a new partial plaque volume (PPV) measure centered on MPT. Total plaque volume (TPV), PPV from a 10-mm segment and MPT were measured using dedicated semi-automated software on 38 plaques from 26 patients. Inter-scan reproducibility was assessed using the t-test, Bland-Altman plots and Pearson's correlation coefficient. There was a mean difference of 0.01 mm in MPT (limits of agreement: -0.45 to 0.42 mm, Pearson's correlation coefficient: 0.96). Both volume measurements exhibited high reproducibility, with PPV being superior (limits of agreement: -35.3 mm3 to 33.5 mm3, Pearson's correlation coefficient: 0.96) to TPV (limits of agreement: -88.2 to 61.5 mm3, Pearson's correlation coefficient: 0.91). The good reproducibility revealed by the present results encourages future studies on establishing plaque quantification as part of cardiovascular risk assessment and for follow-up of disease progression over time.

von Willebrand Factor and Prekallikrein in Plasma Are Associated With Thrombus Volume in Abdominal Aortic Aneurysms.

OBJECTIVES: Disruption of the endothelial lining may be one of the events linking intraluminal thrombus and abdominal aortic aneurysm growth. In the present study, we examined whether von Willebrand factor activity in plasma, contact proteins of blood coagulation, and inflammatory biomarkers may be associated with intraluminal thrombus volume in search of a biochemical marker of endothelial damage and thrombus size. DESIGN: Prospective study, correlating potential endothelial biomarkers and intraluminal thrombus volume acquired by computed tomography angiography. MATERIALS AND METHODS: Plasma was consecutively obtained from 38 patients with asymptomatic infrarenal abdominal aortic aneurysm. von Willebrand factor activity, thrombin generation time, factor XII, and prekallikrein concentration were measured in plasma on automated and in-house platforms. In total, 8 patients were excluded due to ongoing anticoagulant therapy, renal impairment, or nonappearance, thus leaving 30 patients for further analysis. All patients had computed tomography angiography, and intraluminal volume was quantified off-line by OsiriX 6.5. RESULTS: Median intraluminal thrombus volume was 42.7 mL. Spearman correlation analysis revealed a positive correlation between thrombus volume, von Willebrand factor activity (ρ = 0.56, P = .0013), and prekallikrein concentration in plasma (ρ = 0.54, P = .002). CONCLUSION: von Willebrand factor activity and concentration of prekallikrein may both be of importance regarding the evolution of thrombus in abdominal aortic aneurysm and possible biomarkers for aneurysm growth.

In silico analyses of metagenomes from human atherosclerotic plaque samples.

BACKGROUND: Through several observational and mechanistic studies, microbial infection is known to promote cardiovascular disease. Direct infection of the vessel wall, along with the cardiovascular risk factors, is hypothesized to play a key role in the atherogenesis by promoting an inflammatory response leading to endothelial dysfunction and generating a proatherogenic and prothrombotic environment ultimately leading to clinical manifestations of cardiovascular disease, e.g., acute myocardial infarction or stroke. There are many reports of microbial DNA isolation and even a few studies of viable microbes isolated from human atherosclerotic vessels. However, high-resolution investigation of microbial infectious agents from human vessels that may contribute to atherosclerosis is very limited. In spite of the progress in recent sequencing technologies, analyzing host-associated metagenomes remain a challenge. RESULTS: To investigate microbiome diversity within human atherosclerotic tissue samples, we employed high-throughput metagenomic analysis on: (1) atherosclerotic plaques obtained from a group of patients who underwent endarterectomy due to recent transient cerebral ischemia or stroke. (2) Presumed stabile atherosclerotic plaques obtained from autopsy from a control group of patients who all died from causes not related to cardiovascular disease. Our data provides evidence that suggest a wide range of microbial agents in atherosclerotic plaques, and an intriguing new observation that shows these microbiota displayed differences between symptomatic and asymptomatic plaques as judged from the taxonomic profiles in these two groups of patients. Additionally, functional annotations reveal significant differences in basic metabolic and disease pathway signatures between these groups. CONCLUSIONS: We demonstrate the feasibility of novel high-resolution techniques aimed at identification and characterization of microbial genomes in human atherosclerotic tissue samples. Our analysis suggests that distinct groups of microbial agents might play different roles during the development of atherosclerotic plaques. These findings may serve as a reference point for future studies in this area of research.

[Vascular reconstruction of venous occlusion in the lower extremities. Experiences in 12 patients]. / Karkirurgisk rekonstruktion ved venøs okklusion i underekstremiteterne. Erfaringer fra 12 patienter.

INTRODUCTION: This paper describes the late results after surgical reconstruction for deep venous occlusion in the lower extremities. MATERIAL AND METHODS: Twelve patients were treated, two women and 10 men (median age 46, range 17-66 years) over a 6-year period. Seven patients had chronic venous occlusion with venous claudication or ulcer, two had DVT with severely affected limbs, and three were reconstructed, because of tumour involvement. Externally supported ePTFE grafts were used in 11 patients and vein material in the last patient. The median follow-up period was 18 months (range 1-96 months). Evaluation of patency included clinical examination and duplex ultrasound or phlebography. RESULTS: One patient died three weeks postoperatively of multiorgan failure. Another died one year postoperatively of pulmonary metastases from a leiomyosarcoma of the common femoral vein. At follow-up, 50% of the reconstructions had remained open for a median period of five years. DISCUSSION: The results are comparable with those of the literature. The selection of patients requires, in addition to anatomic visualisation of the occluded segment, a haemodynamic demonstration of venous obstruction, i.e. by a pressure gradient across the occluded segment. Surgical reconstruction is possible in the case of a strong indication.

[Interobserver variation in ultrasonographic scanning of carotid stenosis]. / Interobservatørvariation ved UL-scanning af carotisstenose.

INTRODUCTION: Ultrasonic carotid interna scanning is today the gold standard for diagnosing carotid stenosis in patients with stroke or transient ischemic attack. The procedure of ultrasonic carotid interna scanning is not a well-defined procedure. Knowledge of the reproducibility of the method used in own department is important in order to evaluate its usefulness. MATERIAL AND METHODS: Interobserver variability of ultrasonic, duplex carotid artery scanning was examined in 68 carotid arteries in 35 patients by two experienced technologists. The two observers were compared using the kappa (kappa) statistics to analyse the agreement beyond chance. RESULTS: kappa was 0.70 (CI: 0.56-0.83) when the stenoses were categorised in the intervals 0-14%, 15-49%, 50-69%, 70-79%, 80-99% and occlusion. Categorising the stenosis in the clinically relevant intervals 0-69%, 70-79% and occlusion which are used to determine if the patient is a candidate or not to carotid endarterectomy yielded a kappa = 0.92 (CI: 0.81-1.00). DISCUSSION: Low level stenosis accounted for most variability. If state-of-the-art ultrasonic equipment and experienced technologists are used a high level of reproducibility can be achieved.

[Local thrombolysis in proximal deep venous thrombosis of the lower extremity]. / Lokal trombolyse ved proksimal dyb venetrombose i underekstremiteten.

INTRODUCTION: Deep venous thrombosis (DVT) often leads to chronic venous insufficiency and the present study was conducted in order to investigate the effectiveness of catheter-directed thrombolysis in patients with proximal DVT of the lower extremity (iliac vein involved), with respect to recanalisation and maintenance of venous valve function. MATERIAL AND METHODS: A prospective clinical investigation was carried out with puncture of the popliteal vein for continuous infusion of r-alteplase. Twelve patients suffering from recent proximal DVT were treated: In 10 patients the left extremity was affected, in two the right. Three of the 12 patients had factor V Leiden mutation in the heterozygote form, one of whom also had prothrombin mutation in heterozygote form. RESULTS: Ten of the 12 had their venous thrombosis successfully lysed and were discharged with an open venous system in the affected limb. The lysed venous segments remained patent in all ten, with normal venous valve function, as evaluated by Doppler reflux testing. The median follow-up time was five months (range 0-9 months). In one patient, the proximal thrombus (iliac) was lysed successfully, but the femoral vein could not be opened, probably because of an old thrombus remaining from a previous DVT episode. In the other patient, the venous thrombus was lysed successfully, but the vein rethrombosed after one day. DISCUSSION: Catheter-directed thrombolysis appears feasible in patients with recent proximal DVT and the short-term results are good in terms of venous patency and valve function. A randomised trial is necessary to test whether this treatment modality is superior to conventional anticoagulation therapy.