Safe and effective treatment of venous Thromboembolism associated with Cancer: focus on direct Oral Anticoagulants in Asian patients.

Cancer-associated thrombosis (CAT) poses a significant disease burden and the incidence in Asian populations is increasing. Anticoagulation is the cornerstone of treatment, but can be challenging due to the high bleeding risk in some cancers and the high risk of recurrent venous thromboembolism (VTE) in patients with malignancies. Direct oral anticoagulants (DOACs) are well established as first-choice treatments for VTE in non-cancer patients, offering a more convenient and less invasive treatment option than low-molecular-weight heparin (LMWH). Asian patients have exhibited comparable efficacy and safety outcomes with other races in trials of DOACs for VTE in the general population. Although no specific data are available in Asian patients with CAT, results from randomized controlled trials of apixaban, edoxaban, or rivaroxaban versus the LMWH, dalteparin, indicate that DOACs are a reasonable alternative to LMWH for anticoagulation in Asian patients with CAT. This is further supported by analyses of real-world data in Asian populations demonstrating the efficacy and safety of DOACs in Asian patients with CAT. Apixaban, edoxaban, or rivaroxaban are recommended in the most recently updated international guidelines as first-line therapy for CAT in patients without gastrointestinal or genitourinary cancers and at low risk of bleeding. An increased risk of major gastrointestinal bleeding was evident with edoxaban or rivaroxaban, but not apixaban, versus dalteparin in the clinical trials, suggesting that apixaban could be a safe alternative to LMWH in patients with gastrointestinal malignancies. Determining the optimal anticoagulant therapy for patients with CAT requires careful consideration of bleeding risk, tumor type, renal function, drug-drug interactions, financial costs, and patients' needs and preferences.

Indocyanine Green Angiography to Prognosticate Healing of Foot Ulcer in Critical Limb Ischemia: A Novel Technique.

BACKGROUND: To predict wound healing in patients with critical limb ischemia (CLI) is an ongoing issue. Current methods such as ankle-brachial index (ABI), color Doppler and transcutaneous oxygen pressure (TCPO2), and computed tomography angiography are lacking in demonstrating regional perfusion. Indocyanine green angiography (ICGA) has the potential to provide regional perfusion information lacking in other methods. This study was conducted to demonstrate successes of revascularization procedure in CLI patients based on ICGA data. METHODS: A total of 47 patients with grade 2 or grade 3 University of Texas Wound Classification System ischemic foot ulcer undergoing lower limb revascularization procedure were included in this study, from July 2014 to May 2016. ICGA with intravenous 0.1 mg/kg of 0.1% indocyanine green dye was performed before and after revascularization procedure. ICGA data maximum unit, blush time, and blush rate were compared between prerevascularization and postrevascularization data, along with ABI and TCPO2. RESULTS: Out of 47 patients (45 males and 2 females), 43 underwent endovascular revascularization and 4 underwent open procedure. Of all, 76.6% of patients were diabetic and 46.8% were hypertensive. Also, 31.9% had coronary artery disease, 21.2% had history of cerebrovascular disease, 23% had chronic kidney disease, and 74.4% were chronic smokers. A total of 37 patients' ulcer healed completely on follow-up with significant improvement (P < 0.05) in preoperative and postoperative ABI, TCPO2, and ICGA data. Ten patients' ulcer did not heal in the follow-up period. In those 10 patients, preoperative and postoperative ABI and TCPO2 improved, but ICGA data were not improved postoperatively (P > 0.05). CONCLUSIONS: ICGA is an evolving tool to quantify regional perfusion in CLI. ICGA parameters provide qualitative real-time visual images of perfusion in area of interest as well as quantitative information of perfusion.

A Rare Entity: Traumatic Thoracic Aortic Injury in a Patient with Aberrant Right Subclavian Artery.

BACKGROUND: Aberrant right subclavian artery is an uncommon entity incidence ranging from 0.5 to 2.5%. Management of thoracic aortic injury in the presence of such anomalies can be a challenge. We present here a case of traumatic aortic injury, which was incidentally found to have an asymptomatic aberrant right subclavian artery. The patient was managed by an endovascular repair of thoracic aortic injury with an endograft and a right carotid to subclavian artery bypass as a hybrid procedure. METHODS: A 40-year male patient was brought to the emergency in shock with an alleged history of road traffic accident an hour back. After initial resuscitation as per advance trauma life support protocol, imaging revealed thoracic aortic injury with aberrant right subclavian artery with multiple rib and bilateral humerus fracture. After primary stabilization of arm fractures, the patient was shifted to a hybrid operation room. As the aortic injury was within 10 mm of the origin of both subclavian arteries, it was decided to cover the origin of both subclavian arteries and land the endograft distal to the left carotid artery origin. Since there was a right dominant vertebral artery on imaging, right carotid to right subclavian artery bypass was done with expanded polytetrafluoroethylene graft to prevent posterior circulatory stroke along with thoracic endovascular aortic repair to seal the thoracic aortic injury. RESULTS: After endovascular repair of thoracic aortic injury, left subclavian artery perfusion was maintained through left vertebral artery; and hence, revascularization of left subclavian artery was deferred. After management of all fractures, the patient was discharged 3 weeks after the date of admission without any complications. At 6 months follow-up, patient was stable and images showed patent bypass graft and sealed aortic injury. CONCLUSIONS: In a trauma setting with multiple injuries, hybrid procedure with a thoracic endograft is associated with low mortality and morbidity; hence, it is the treatment of choice for thoracic aortic injury over open surgical repair. A hybrid suite can be life and time saving in situations which mandate simultaneous endovascular repair along with surgical revascularization when indicated, especially in cases with aberrant aortic arch anatomy.

Administration of Adult Human Bone Marrow-Derived, Cultured, Pooled, Allogeneic Mesenchymal Stromal Cells in Critical Limb Ischemia Due to Buerger's Disease: Phase II Study Report Suggests Clinical Efficacy.

Critical limb ischemia (CLI) due to Buerger's disease is a major unmet medical need with a high incidence of morbidity. This phase II, prospective, nonrandomized, open-label, multicentric, dose-ranging study was conducted to assess the efficacy and safety of i.m. injection of adult human bone marrow-derived, cultured, pooled, allogeneic mesenchymal stromal cells (BMMSC) in CLI due to Buerger's disease. Patients were allocated to three groups: 1 and 2 million cells/kg body weight (36 patients each) and standard of care (SOC) (18 patients). BMMSCs were administered as 40-60 injections in the calf muscle and locally, around the ulcer. Most patients were young (age range, 38-42 years) and ex-smokers, and all patients had at least one ulcer. Both the primary endpoints-reduction in rest pain (0.3 units per month [SE, 0.13]) and healing of ulcers (11% decrease in size per month [SE, 0.05])-were significantly better in the group receiving 2 million cells/kg body weight than in the SOC arm. Improvement in secondary endpoints, such as ankle brachial pressure index (0.03 [SE, 0.01] unit increase per month) and total walking distance (1.03 [SE, 0.02] times higher per month), were also significant in the group receiving 2 million cells/kg as compared with the SOC arm. Adverse events reported were remotely related or unrelated to BMMSCs. In conclusion, i.m. administration of BMMSC at a dose of 2 million cells/kg showed clinical benefit and may be the best regimen in patients with CLI due to Buerger's disease. However, further randomized controlled trials are required to confirm the most appropriate dose. Stem Cells Translational Medicine 2017;6:689-699.

Role of hybrid operating room in surgery for the right atrial thrombus, pulmonary thrombi, and ventricular septal rupture after myocardial infarction.

Free-floating right heart thrombi are uncommon and need emergency treatment in view of their tendency to dislodge and cause pulmonary embolism. We report a successful surgical management of a patient who had large mobile right atrial thrombus, bilateral pulmonary thrombi, coronary artery disease, and postmyocardial infarction ventricular septal rupture (VSR). The patient underwent coronary angiography, inferior vena cava filter placement, removal of thrombi from the right atrium and pulmonary arteries, repair of VSR, and coronary artery bypass graft surgery in a hybrid operating room.

Training in dialysis access - charting future success.

PURPOSE: Medical education and training in dialysis access skills remains complex and inadequate as learners come from diverse backgrounds and from various specialties so that appropriate training is limited. As a result, a system of progressive education including live lectures, and hands on training has emerged, but there is controversy as to what constitutes the best educational model. METHODS: Presently there is no recognized or structured training in vascular access during residency or fellowships. Here we present a model of dialysis access training for beginner to advanced surgeons. RESULTS: A structured hands-on and didactic surgery training certification course consisting of a one week curriculum with 49 hours of ACCME credit hours has been in effect for one year. The learning impact and the performance outcome are high but with limited attendance capacity. Pre- and post- training test results attest to training effectiveness. To increase access, an off-site training curriculum has been initiated, entailing 1-2 days (8-15 credit hours) consisting of didactic lectures and surgical training. This teaching module has moderate learning impact for 50-100 attendees.Finally, a tiered, web-based training curriculum (10 ACCME credit hours) can accommodate an unlimited number of learners, but has a lower skills learning impact. CONCLUSIONS: The future dialysis access training must also accommodate learners with diverse individual backgrounds, and different levels of professional (skill) development. To be effective and accessible, a variety of educational system, for example on site or web based is needed. Collaborative initiatives for global dialysis access training are currently underway.

Double Barrel In Situ Recanalization of Thrombosed Nonretrievable IVC filter.

We report a case of endovascular recanalization of complete thrombotic occlusion of the inferior vena cava (IVC) and bilateral iliac veins using the architectural knowledge of the in situ permanent IVC filter in a 23-year-old male. The infrarenal permanent IVC filter was TRAPEASE permanent vena cava filter (Cordis) placed at an outstation hospital for pulmonary embolism. Being permanent variant of filter, percutaneous removal was not possible. The patient had severe venous claudication and an attempt to recanalize the blocked filter was considered, in view of the age no justifiable indication for a long-term filter. After pharmacomechanical catheter-directed thrombolysis, there was residual focal flow-limiting thrombus within the filter. The design of the Trapease Cordis filter was instrumental in our decision to attempt to recanalize the filter in situ using 2 parallel stents with the filter struts as anchoring pillars in a double-barrel alignment. In similar cases of persistent Trapease filter-related thrombotic occlusion of the IVC, this double barrel in situ recanalization shall be a viable alternative to the well-described technique of crushing the filter and recanalizing it with a single stent.

Consensus on Management of Deep Vein Thrombosis with Emphasis on NOACs (Non-Vitamin K Antagonist Oral Anticoagulants): Recommendations from Inter-Disciplinary Group of Indian Experts.

It is estimated that around 2.5 lac patients are identified as having an acute venous thrombo-embolic event in India annually. This includes patients with deep vein thrombosis and pulmonary embolism, and is estimated to result in more than 3.7 lacs deaths each year in European countries. The 'Consensus on Management of Deep Vein Thrombosis with Emphasis on NOACs (Non-Vitamin K Antagonist Oral Anticoagulants): Recommendations from Inter-Disciplinary Group of Indian Experts' position paper was developed to assist clinicians and institutions with an evidence-based approach to the diagnosis and treatment of acute deep vein thrombosis patients. Key to the evaluation of patients with suspected deep vein thrombosis is the use of the clinician's clinical evaluation with the help of pre-test probability tools as well as judicious use of objective diagnostic tests. Our hope is that we have supplemented clinicians' clinical acumen, and assisted them and their health systems in developing best practice approaches to this ever-interesting population of patients. The Deep Vein Thrombosis Consensus Working Group welcomes your inputs on how improvements might be made on this paper in the future.

CYP2C9, VKORC1, CYP4F2, ABCB1 and F5 variants: influence on quality of long-term anticoagulation.

AIMS: The study aims to evaluate the impact of genetic, demographic and clinical data on various measures of outcome of anticoagulation quality in patients. PATIENTS AND METHODS: The study consisted of 310 patients receiving long-term oral anticoagulation therapy in our hospital. Apart from demographic and clinical variables, 21 SNPs (in 7 genes) were analyzed and compared with the outcomes of anticoagulation therapy. Various outcomes that were measured are; supra therapeutic INRs (INR >3, >6), anticoagulation stabilization, time taken to stabilize and proportion of INRs within (2-3), above (>3) and below (<2) therapeutic range. RESULTS: Supra therapeutic INRs were influenced by CYP2C9*2, *3, CYP4F2 rs2108622, VKORC1-1639G>A, 1173C>T, rs55894764 along with concomitant drugs, smoking, body weight and height. Persistently fluctuating INRs/absolute instability correlated with VKORC1-1639G>A, gender, height and body mass index. The time taken to stabilize was associated with CYP4F2 rs2108622, CYP2C9*14, smoking, clinical indication and concomitant drugs. The overall distribution of INR was influenced by variants in CYP4F2 rs2108622, CYP2C9*3, rs9332230, VKORC1 1173C>T, -1639G>A, rs55894764, ABCB1 rs2032582, rs1128503, rs1045642 and F5 rs6025, age, smoking and concomitant drugs. CONCLUSIONS: Knowledge of factors influencing the quality of long term anticoagulation can help clinicians to customize therapy either by dose variation, therapy with alternate choice of drug, concurrent heparin therapy and/or frequent INR monitoring.

A double blind randomized placebo controlled phase I/II study assessing the safety and efficacy of allogeneic bone marrow derived mesenchymal stem cell in critical limb ischemia.

BACKGROUND: Peripheral vascular disease of the lower extremities comprises a clinical spectrum that extends from no symptoms to presentation with critical limb ischemia (CLI). Bone marrow derived Mesenchymal Stem Cells (BM- MSCs) may ameliorate the consequences of CLI due to their combinatorial potential for inducing angiogenesis and immunomodulatory environment in situ. The primary objective was to determine the safety of BM- MSCs in patients with CLI. METHODS: Prospective, double blind randomized placebo controlled multi-center study was conducted in patients with established CLI as per Rutherford classification in category II-4, III-5, or III-6 with infra-inguinal arterial occlusive disease and were not suitable for or had failed revascularization treatment. The primary end point was incidence of treatment - related adverse events (AE). Exploratory efficacy end points were improvement in rest pain, increase in Ankle Brachial Pressure Index (ABPI), ankle pressure, healing of ulcers, and amputation rates. Twenty patients (BM-MSC: Placebo = 1:1) were administered with allogeneic BM-MSCs at a dose of 2 million cells/kg or placebo (PlasmaLyte A) at the gastrocnemius muscle of the ischemic limb. RESULTS: Improvement was observed in the rest pain scores in both the arms. Significant increase in ABPI and ankle pressure was seen in BM-MSC arm compared to the placebo group. Incidence of AEs in the BM-MSC arm was 13 vs. 45 in the placebo arm where as serious adverse events (SAE) were similar in both the arms (5 in BM-MSC and 4 in the placebo group). SAEs resulted in death, infected gangrene, amputations in these patients. It was observed that the SAEs were related to disease progression and not related to stem cells. CONCLUSION: BM-MSCs are safe when injected IM at a dose of 2 million cells/kg body weight. Few efficacy parameters such as ABPI and ankle pressure showed positive trend warranting further studies. TRIAL REGISTRATION: NIH website (http://www.clinicaltrials.gov/ct2/show/NCT00883870).

Implication of novel CYP2C9*57 (p.Asn204His) variant in coumarin hypersensitivity.

INTRODUCTION: Polymorphisms in CYP2C9 can vary the rate of metabolic clearance of oral anticoagulants, risking toxicity in patients. The present study focused on exploring the genetic etiology of idiopathic hyper sensitivity to coumarin anticoagulants in a patient who presented with multiple bleeding episodes and supra-elevated International Normalized Ratios. MATERIALS AND METHODS: Bidirectional gene sequencing of CYP2C9 and VKORC1 was carried out. Using allele-specific polymerase chain reaction, the identified novel variant was genotyped in 309 patients on anticoagulation therapy. The pharmacoproteomic significance of the novel genetic variant was elucidated by structural demonstration of binding of coumarin molecules within the mutant CYP2C9 204His protein model and in silico bioinformatic evolutionary analyses. Three-dimensional structure model of the mutant protein was constructed on the basis of the published X-ray crystal structure of human CYP2C9 protein (Protein Data Bank, 1R9O). RESULTS: The patient was identified to have a novel heterozygous missense mutation in exon 4 of CYP2C9 gene (g.9172A > C; p.Asn204His; CYP2C9*57). The variant was absent in the 309 genotyped patients. In silico bioinformatic analyses indicated the variant to have a deleterious effect on the protein. Analysis of 3D structure model of the mutant protein revealed that the substituted His204 led to restricted binding of the coumarin drug within the binding site of CYP2C9 enzyme, thereby inhibiting its metabolic clearance and thus explaining the enhanced pharmacologic effect and bleeding in the patient. CONCLUSIONS: The study elucidates the structurally deleterious role of the novel CYP2C9*57 missense mutation in coumarin toxicity.

Low-molecular-weight heparin and mortality in acutely ill medical patients.

BACKGROUND: Although thromboprophylaxis reduces the incidence of venous thromboembolism in acutely ill medical patients, an associated reduction in the rate of death from any cause has not been shown. METHODS: We conducted a double-blind, placebo-controlled, randomized trial to assess the effect of subcutaneous enoxaparin (40 mg daily) as compared with placebo--both administered for 10±4 days in patients who were wearing elastic stockings with graduated compression--on the rate of death from any cause among hospitalized, acutely ill medical patients at participating sites in China, India, Korea, Malaysia, Mexico, the Philippines, and Tunisia. Inclusion criteria were an age of at least 40 years and hospitalization for acute decompensated heart failure, severe systemic infection with at least one risk factor for venous thromboembolism, or active cancer. The primary efficacy outcome was the rate of death from any cause at 30 days after randomization. The primary safety outcome was the rate of major bleeding during and up to 48 hours after the treatment period. RESULTS: A total of 8307 patients were randomly assigned to receive enoxaparin plus elastic stockings with graduated compression (4171 patients) or placebo plus elastic stockings with graduated compression (4136 patients) and were included in the intention-to-treat population. The rate of death from any cause at day 30 was 4.9% in the enoxaparin group as compared with 4.8% in the placebo group (risk ratio, 1.0; 95% confidence interval [CI], 0.8 to 1.2; P=0.83). The rate of major bleeding was 0.4% in the enoxaparin group and 0.3% in the placebo group (risk ratio, 1.4; 95% CI, 0.7 to 3.1; P=0.35). CONCLUSIONS: The use of enoxaparin plus elastic stockings with graduated compression, as compared with elastic stockings with graduated compression alone, was not associated with a reduction in the rate of death from any cause among hospitalized, acutely ill medical patients. (Funded by Sanofi; LIFENOX ClinicalTrials.gov number, NCT00622648.).

Endovascular treatment for peripheral pulmonary artery aneurysm.

A 42-year-old male presented with recurrent hemoptysis owing to a leaking peripheral pulmonary artery aneurysm. He was treated with selective coil embolization of the right posterior basal segmental artery to achieve hemostasis. This case is reported for its unsuspected presentation and rarity and to highlight the use of catheter coil embolization to achieve endovascular exclusion of the aneurysm from pulmonary circulation.

Prevalence of hyperhomocysteinemia in vascular disease: comparative study of thrombotic venous disease vis-à-vis occlusive arterial disease.

Studies on hyperhomocysteinemia in vascular occlusive disease have included mostly patients with arterial occlusion. However, more recent studies have included cases of venous occlusive disease as well. Our present study is aimed at comparing the prevalence of hyperhomocysteinemia in venous occlusive disease vis-à-vis arterial occlusive disease in the North Indian urban population. Homocysteine was estimated by chemiluminescent immunoassay in 205 normal controls and 536 patients, 244 presenting with arterial occlusion and 292 with venous thrombotic disease. The mean homocysteine in patients with arterial occlusion was 21.79 +/- 0.09 micromol/L (mean +/- standard error of measurement), in patients with venous thrombosis was 25.53 +/- 0.1 micromol/L, and in controls was 11.33 +/- 0.18 micromol/L. The prevalence of hyperhomocysteinemia (> 15 micromol/L) was 56.38% in arterial occlusive disease and 54.64% in venous thrombosis. In patients with peripheral vascular occlusive disease, patients with deep venous thrombosis (DVT) had the highest mean homocysteine level (25.51 micromol/L), which was even higher (32.14 micromol/L) when associated with pulmonary embolism (PE). There is a high prevalence of hyperhomocysteinemia in arterial and venous occlusive disease. Hence, in all patients with vascular occlusive disease, hyperhomocysteinemia should be elucidated and treated. In addition, long-term follow-up is required to ascertain whether the reduction in homocysteine decreases the thrombotic events and whether homocysteine levels can actually be of prognostic or predictive value in cases of DVT with PE.

Pulmonary embolism: a frequent occurrence in Indian patients with symptomatic lower limb venous thrombosis.

OBJECTIVE: Pulmonary embolism (PE) is the most severe complication of deep venous thrombosis (DVT). There have been very few studies to assess the prevalence of PE in Asian patients. The objective of this study was to define the prevalence of PE in patients presenting with suspected lower limb DVT. METHODS: This was a prospective cohort study at Sir Ganga Ram Hospital, a large multispecialty hospital in New Delhi, India. From January 2001 to July 2004, 1,552 consecutive inpatients and outpatients who presented with clinically suspected lower limb DVT were enrolled in the study. Combined ascending radionuclide venography and lung perfusion scan was performed in all patients. Patients with evidence of pulmonary perfusion defects underwent ventilation lung scan. RESULTS: Radionuclide venography-detectable DVT was noted in 744 patients, of whom 521 (70%) had suprapopliteal DVT. Of patients with DVT, 294 (39.5%) showed a high-probability lung scan and 135 (18.1%) had an intermediate-probability lung scan. Overall, 47% of patients with a high-probability scan had no clinical manifestations suggestive of PE. CONCLUSION: PE occurs frequently in Indian patients with symptomatic DVT. Increasing awareness will provide us with clearer ideas about the prevalence of venous thromboembolism in Asian countries.