Methods, design, and initial results of an angiographic core lab from VOYAGER-PAD.

Background: Anatomy is critical in risk stratification and therapeutic decision making in coronary disease. The relationship between anatomy and outcomes is not well described in PAD. We sought to develop an angiographic core lab within the VOYAGER-PAD trial. The current report describes the methods of creating this core lab, its study population, and baseline anatomic variables. Methods: Patients undergoing lower-extremity revascularization for symptomatic PAD were randomized in VOYAGER-PAD. The median follow up was 2.25 years. Events were adjudicated by a blinded Clinical Endpoint Committee. Angiograms were collected from study participants; those with available angiograms formed this core lab cohort. Angiograms were scored for anatomic and flow characteristics by trained reviewers blinded to treatment. Ten percent of angiograms were evaluated independently by two reviewers; inter-rater agreement was assessed. Clinical characteristics and the treatment effect of rivaroxaban were compared between the core lab cohort and noncore lab participants. Anatomic data by segment were analyzed. Results: Of 6564 participants randomized in VOYAGER-PAD, catheter-based angiograms from 1666 patients were obtained for this core lab. Anatomic and flow characteristics were collected across 16 anatomic segments by 15 reviewers. Concordance between reviewers for anatomic and flow variables across segments was 90.5% (24,417/26,968). Clinical characteristics were similar between patients in the core lab and those not included. The effect of rivaroxaban on the primary efficacy and safety outcomes was also similar. Conclusions: The VOYAGER-PAD angiographic core lab provides an opportunity to correlate PAD anatomy with independently adjudicated outcomes and provide insights into therapy for PAD. (ClinicalTrials.gov Identifier: NCT02504216).

Fatal heat stroke based on foudroyant irreversible multiple organ dysfunction in German summer.

Objectives: Heat stroke is a serious condition that might lead from moderate organ impairment to multiple organ dysfunction syndrome. Appropriate diagnosis-finding, fast initiation of cooling and intensive care are key measures of the initial treatment. Scientific case report based on i) clinical experiences obtained in the clinical management of a particularly rare case and ii) selected references from the medical scientific literature. Case presentation: We present a case of a young and healthy construction worker who suffered from an exertional heat stroke with a body core temperature exceeding 42 °C by previous several hour work at 35 °C ambient temperature. Heat stroke was associated with foudroyant, not reversible multiple organ dysfunction syndrome, in particular, early disturbed coagulation, microcirculatory, liver and respiratory failure, and subsequent fatal outcome despite immediate diagnosis-finding, rapid external cooling and expanded intensive care management. Conclusions: Basic knowledge on an adequate diagnosis(-finding in time) and treatment of heat stroke is important for (almost each) physician in the summertime as well as is essential for the initiation of an appropriate management. Associated high morbidity and mortality rates indicate the need for implementation of standard operation protocols.

Acute Abdominal Pain as a Result of an Isolated Left Ovarian Vein Thrombosis.

Ovarian vein thrombosis (OVT) is a rare thromboembolic condition. It involves the right ovarian vein in 70-80% of cases. The risk factors for the development of OVT are pregnancy or puerperium, hormone therapy with estrogen, recent surgery or hospitalization, malignancy, pelvic inflammatory diseases, thrombophilia and idiopathic OVT. We present a rare case of left OVT in a young, non-pregnant woman in her 30 s. A high degree of suspicion is necessitated in patients with the triad of young-middle-aged female, pain abdomen in lower quadrant and hematuria to diagnose OVT. Contrast enhanced computer tomography (CT-venography) is the diagnostic modality of choice. The patient was initially treated with low molecular weight heparin and then switched to direct oral anticoagulants. At 6-monthsfollow-up the patient was free from any symptoms.

The Role of Anticoagulants and Platelet Aggregation Inhibitors in the Treatment of Pseudoaneurysms and Risk of Venous Thrombosis.

Pseudoaneurysms (PSA) are one of the most common complications after arterial punctures. This retrospective study examined whether platelet aggregation inhibitors (APT) or anticoagulants (AC) lower the success rates of PSA treatment. A total of 468 patients with PSA were retrospectively analyzed between 2010 and 2018, and 238 were included in the study. Despite co-medication with APT or AC, thrombin injection (TI) was superior to compression bandage (CB) therapy in treating PSA (TIwAC 79 vs CBwAC 51%; P = .004 and TIwAPT 93 vs CBwAPT 54%; P = .001). There was no decrease in PSA-associated thrombosis in patients requiring anticoagulation after TI. The success rates of the TI and CB groups were compared in patients with and without AC therapy, and the latter was significantly lower. A reduced success rate was not observed in CB therapy patients requiring APT. In contrast, better results were seen in the TI group. Regarding PSA treatment, TI therapy is significantly superior to CB, including in patients requiring concomitant AC or APT therapy. PSA-associated thrombosis also occurs in patients requiring anticoagulation, and sonography should be performed. Concomitant medication use with APT does not significantly influence PSA therapy success or prevention of PSA-associated thrombosis.

High incidence of deep vein thrombosis during the treatment of pseudoaneurysms - a retrospective nonrandomized study.

Background: Pseudoaneurysms (PSAs) are concerning complications after arterial invasive interventions. Therapeutic options include manual ultrasound-assisted compression, pressure dressings, surgical intervention and thrombin injection. Compression of neighboring veins is obvious. However, the incidence of deep vein thrombosis (DVT) in patients with PSA has not previously been investigated. Patients and methods: In this retrospective, nonrandomized study 238 patients with PSA were analyzed from 2013 to 2018. In 149 patients, all of the parameters were complete for participating. PSAs were treated according to the local standard therapy with either ultrasound-guided compression followed by compression bandage or thrombin injection. Treatment success was evaluated 24 hours later, and the venous system was examined for the presence of DVT. Results: Peripheral DVT was found in 25.4% patients after ultrasound-assisted compression and subsequent pressure bandages, but only 6.4% of patients had DVT after thrombin injection (p = 0.013). Lower leg veins, particularly veins of the crural muscles, were primarily affected. Significantly more PSAs were successfully treated without the occurrence of DVT in the thrombin injection group compared to the compression group (93.6 vs. 69.0%; p = 0.001). Conclusions: Our study revealed that the use of thrombin injections resulted in a significantly lower rate of postinterventional DVT and a higher total number of successfully treated PSAs compared to compression therapy.

[How to anticoagulate elderly and fragile patients?] / Wie antikoaguliert man ältere und fragile Patienten?

Risks of thrombosis, bleeding and renal impairment are increasing with age. The efficacy and safety of the direct oral anticoagulants (DOACs) in fragile patients (age > 75 years and/or creatinine clearance levels < 50 ml/min and/or body weight below 50 kg) with indication for anticoagulation is one of the most challenging topic in cardiovascular medicine. New registry data from subgroup analyses of landmark studies and registries point towards to superiority of DOACs. This article summarizes new insights and describes pathways for anticoagulation in fragile patients.

Direct Oral Anticoagulants for the Treatment of Acute Venous Thromboembolism Associated with Cancer: A Systematic Review and Meta-Analysis.

BACKGROUND: International guidelines have endorsed the use of edoxaban or rivaroxaban as an alternative to low-molecular-weight heparin (LMWH) for the treatment of acute venous thromboembolism (VTE) in cancer patients. Recently, a large randomized controlled trial of apixaban versus dalteparin in patients with cancer was completed. We performed an updated meta-analysis to assess the efficacy and safety of direct oral anticoagulants (DOACs) versus LMWH in patients with cancer-associated VTE. METHODS: MEDLINE, EMBASE, and CENTRAL (Cochrane Controlled Trials Registry) were systematically searched up to March 30, 2020 for randomized controlled trials comparing DOACs versus LMWH for the treatment of VTE in patients with cancer. The two coprimary outcomes were recurrent VTE and major bleeding at 6 months. Data were pooled by the Mantel-Haenszel method and compared by relative risk ratios (RRs) and 95% confidence intervals (CIs). RESULTS: Four randomized controlled studies (2,894 patients) comparing apixaban, edoxaban, or rivaroxaban with dalteparin were included in the meta-analysis. Recurrent VTE occurred in 75 of 1,446 patients (5.2%) treated with oral factor Xa inhibitors and in 119 of 1,448 patients (8.2%) treated with LMWH (RR 0.62; 95% CI 0.43-0.91; I 2, 30%). Major bleeding occurred in 62 (4.3%) and 48 (3.3%) patients receiving oral factor Xa inhibitors or LMWH, respectively (RR 1.31; 95% CI 0.83-2.08; I 2, 23%). CONCLUSION: In patients with cancer-associated VTE, oral factor Xa inhibitors reduced the risk of recurrent VTE without a significantly higher likelihood of major bleeding at 6 months compared with LMWH.

[Modern Finding-Specific and Patient-Adapted Management of Peripheral Pseudoaneurysms after Arterial Access]. / Das moderne befund- und patientenadaptierte Management von peripheren Pseudoaneurysmen nach arteriellem Zugang.

Aside from haematomas, pseudoaneurysms (PSA) are considered the most frequent complications after catheter-guided interventions. AIM AND METHOD: Narrative compact short overview to describe aetiopathogenesis and characteristics of pseudoaneurysms and the options for diagnostic measures, therapy and its complications. RESULTS: Aetiopathogenesis: via the closed access site, the puncture channel, there is continuous bleeding out of the vessel which forms a pseudoaneurysm-associated cavity within the perivascular tissue. This is not surrounded by a regular vascular wall as in true aneurysms but is only formed by the surrounding tissue structures. However, this border is not sufficient and the pseudoaneurysm may extend, with diffuse bleeding episodes into the tissue. Thus, surrounding structures such as nerves and veins can be compressed by the expanding pseudoaneurysm, which can lead to irreversible damage. Diagnostic measures: duplex ultra-sonography absolutely predominant. CT-A, MR-A and DSA for specific problems and clinical case characteristics (e.g., accompanying diseases etc.) - DSA is to be linked with the option of image-guided intervention during the same session. THERAPY: by manual compression and subsequent dressing with compression, ultrasound-guided compression, thrombin injection and surgical intervention, there are several therapeutic measures for appropriate selection according to the specific need. Ultrasound-guided compression should be immediately used since it is highly efficient and widely available. In addition to compression, thrombin can be injected into the pseudoaneurysm-preserving nerval structures and tissue from alterations. This provides much better occlusion rates but is more demanding. Surgical intervention is the most efficient approach to occlude a pseudoaneurysm but is demanding and can be associated with complications such as disturbances of wound healing in altered tissue and the longest hospital stay. Alternative approaches have not been established yet. CONCLUSION: The diagnostic and therapeutic management of pseudoaneurysms for different findings and patients can be considered a great challenge, and requires an experienced angiologist or vascular surgeon.

Oral Anticoagulation in the Elderly and Frail.

The proportion of elderly patients will increase substantially over the next decades, and both atrial fibrillation (AF) and venous thromboembolism (VTE) are more common in the elderly. Age is a risk factor not only for stroke and thromboembolism but also for bleeding, particularly in frail patients, in whom numerous pathophysiological changes occur that alter drug kinetics and toxicity of standard doses of oral anticoagulants (OACs). AF trials showed that the relative benefits of direct OACs (DOACs) also applied to elderly patients, and due to their higher risk this translates into a higher absolute risk reduction compared with vitamin K antagonists, suggesting that DOACs are the better choice. All DOACs-at varying extent-are eliminated via the kidney and it is crucial to evaluate renal function at initiation and during follow-up, especially for dabigatran. The fear of falls is a common reason against OAC. However, there is still a benefit with OAC, particularly with DOACs given the lower risk of intracranial hemorrhage. Polypharmacy represents a common challenge, nevertheless DOACs and warfarin were classified as beneficial. Nonetheless, attempts should be undertaken to reduce comedication, and drug-drug interactions should be assessed. Coadministration of platelet inhibitors increases bleeding risk and should be avoided. In conclusion, elderly and frail patients requiring anticoagulation for AF or VTE are at higher risk of adverse outcomes, but also have a higher absolute benefit from OAC. Important practical aspects to improve efficacy and safety in this challenging population are summarized in this overview.

VEGF-A-Cleavage by FSAP and Inhibition of Neo-Vascularization.

Alternative splicing leads to the secretion of multiple forms of vascular endothelial growth factor-A (VEGF-A) that differ in their activity profiles with respect to neovascularization. FSAP (factor VII activating protease) is the zymogen form of a plasma protease that is activated (FSAPa) upon tissue injury via the release of histones. The purpose of the study was to determine if FSAPa regulates VEGF-A activity in vitro and in vivo. FSAP bound to VEGF165, but not VEGF121, and VEGF165 was cleaved in its neuropilin/proteoglycan binding domain. VEGF165 cleavage did not alter its binding to VEGF receptors but diminished its binding to neuropilin. The stimulatory effects of VEGF165 on endothelial cell proliferation, migration, and signal transduction were not altered by FSAP. Similarly, proliferation of VEGF receptor-expressing BAF3 cells, in response to VEGF165, was not modulated by FSAP. In the mouse matrigel model of angiogenesis, FSAP decreased the ability of VEGF165, basic fibroblast growth factor (bFGF), and their combination, to induce neovascularization. Lack of endogenous FSAP in mice did not influence neovascularization. Thus, FSAP inhibited VEGF165-mediated angiogenesis in the matrigel model in vivo, where VEGF's interaction with the matrix and its diffusion are important.

Clinical improvement and enhanced collateral vessel growth after xenogenic monocyte transplantation.

Background: Monocytes (Mo) are the most important mediators in arteriogenesis. Previous results from our group demonstrated the great potential of allogenic Mo transplantation for improving collateral vessel growth, which appeared to be due to a considerable host vs. graft reaction. To prove this hypothesis and introduce this new method in clinical practice, we performed transplantation of human Mo (HuMo) in a mouse model. Methods and results: We ligated the femoral artery of BALB/c mice and transplanted Mo via the tail vein. Perfusion was measured by laser Doppler perfusion imaging (LDPI). We also performed clinical scoring based on behavior, wound healing, signs of inflammation and mobility of the ligated extremity. Finally, arteriogenesis and angiogenesis were examined histologically and by quantitative RT-PCR of the hind limb musculature. LDPI increased within one week after ligation when HuMo were transplanted and increased further up to day 21 (0.63±0.12 (n=12) in HuMo vs. 0.50±0.12 (n=17) in the control group (P<0.01)). A histological evaluation showed significantly more collateral arteries within the adductor muscles after HuMo transplantation. The promotion of collateral vessel growth after HuMo transplantation resulted in better clinical scores (0.33±0.26 (n=12) vs. 3.3 (n=9), SEM; P<0.01). Conclusions: Transplantation of HuMo improves collateral vessel growth and clinical outcomes in mice. These results verify our hypothesis that controlled triggering of the inflammatory mechanism resulted in collateral vessel growth by a local host vs. a graft reaction in the ischemic hind limbs and could represent a further step in the development of a clinical strategy for promoting arteriogenesis.

Influence of the plasminogen activator system on necrosis in acute myocardial infarction: analysis of urokinase- and urokinase receptor-knockout mouse models.

Serine proteases and G-protein-coupled receptors have been studied extensively as effectors of cell death. However, their roles in myocardial infarction have not been determined. In this study, we investigated the influence of the plasminogen activator system involving urokinase and urokinase receptor on necrosis after acute myocardial infarction. Myocardial infarction and reperfusion were induced in mouse hearts using the in vitro Langendorff model. DNA fragmentation and cleaved caspase-3 activity in urokinase- (uPA-/-) and urokinase receptor-knockout mice (uPAR-/-) were determined and compared with those in wild-type mice using in situ nick-end DNA labeling (TUNEL) and enzyme-linked immunosorbent assays, respectively. Infarct sizes were determined using propidium iodide and fluorescent microspheres. Following regional ischemia and reperfusion, a significant increase in the number of TUNEL-positive nuclei was observed in the ischemic zone in mouse hearts and to a lesser degree in regions remote from the ischemic area in wild-type, uPAR-/-, and uPA-/- groups compared with those in directly removed hearts. No significant differences were observed between uPAR-/- and wild-type mice. Conversely, a significant reduction in DNA fragmentation was observed in ischemic and nonischemic regions after acute myocardial infarction in uPA-/- mice when compared with that in wild-type and uPAR-/- groups. The resulting infarct sizes were significantly smaller in uPA-/- mice than in uPAR-/- and wild-type mice. These data demonstrated the involvement of uPA, but not uPAR, in protecting against necrosis during acute myocardial infarction.