Laboratory Monitoring of Non-Vitamin K Antagonist Oral Anticoagulants and Their Use in Special Populations / 中山大学学报(医学科学版)

In the past few decades， heparin and warfarin have been the main anticoagulants used to treat and prevent venous thromboembolism. Recent studies at home and abroad have shown that non-vitamin K antagonist oral anticoagulants （NOACs） have similar or better efficacy and safety in the prevention and treatment of venous thromboembolism and non-valvular atrial fibrillation. NOACs do not require routine coagulation monitoring when used at a fixed dose. However， in special populations or specific scenarios such as emergency surgery， etc.， an overdose or underdose and abnormal metabolism of NOACs may reduce the drug efficacy and safety， so monitoring and evaluating the anticoagulant effect of NOACs is more conducive to the prognosis of patients.This paper briefly reviewed the common laboratory monitoring methods of NOACs and their use in special populations， aiming to explain different monitoring methods for different NOACs and the applicability of NOACs in special populations， and hoping to provide reference for clinical standard monitoring and use of NOACS.

Perioperative Management of Patients with Prosthetic Heart Valves?A Narrative Review

Worldwide, about 13% of the 200,000 annual recipients of prosthetic heart valves (PHV) present for various surgical procedures. Also, more and more females are opting for pregnancies after having PHV. All patients with PHV present unique challenges for the anesthesiologists, surgeons and obstetricians (in case of deliveries). They have to deal with the perioperative management of anticoagulation and a host of other issues involved. We reviewed the English language medical literature relevant to the different aspects of perioperative management of patients with PHV, particularly the guidelines of reputed societies that appeared in the last 20 years. Regression of cardiac pathophysiology following valve replacement is variable both in extent and timeline. The extent to which reverse remodeling occurs depends on the perioperative status of the heart. We discussed the perioperative assessment of patients with PHV, including focused history and relevant investigations with the inferences drawn. We examined the need for prophylaxis against infective endocarditis and management of anticoagulation in such patients in the perioperative period and the guidelines of reputed societies. We also reviewed the conduct of anesthesia, including general and regional anesthesia (neuraxial and peripheral nerve/plexus blocks) in such patients. Finally, we discussed the management of delivery in this group of high?risk patients. From the discussion of different aspects of perioperative management of patients with PHV, we hope to guide in formulating the comprehensive plan of management of safe anesthesia in such patients.

Resolution of Primary Aortic Thrombosis after Dabigatran therapy—A New Hope for the Rare and Old Disease

The primary aortic thrombosis (PAT) is an uncommon noncardiac cause of distal peripheral embolization to lower extremities. Also, this condition develops in the absence of extensive atherosclerosis of aorta or abnormal dilatation like aneurysm of the aorta. In most of the cases, there was either no or minimal atherosclerosis of the aorta. The disease can involve any part of the aorta, but in most of the cases, the thoracic aorta below the origin of the left subclavian artery followed by the infrarenal portion of the abdominal aorta was the most common site of involvement. In our case, there was extensive thrombosis starting from the lower part of the thoracic aorta extending across both the renal arteries up to the aortic bifurcation without any underlying aortic pathology or hypercoagulable disease. There are no guidelines for the management of the PAT, but our experience is based on few case series, case reports, and meta-analysis where there are variable success rate using conservative medical management, endovascular procedure, or surgical thrombectomy. Vitamin K antagonist was the drug of choice in all the cases as a part of conservative medical management or used to prevent recurrence after the endovascular or surgical procedure. We present a case of PAT where the use of dabigatran leads to complete resolution and prevented the recurrence of the disease during two-year follow-up, which is the first and unique case report of the literature.

Antithrombotic Strategy in Atrial Fibrillation Patients Undergoing Percutaneous Coronary Intervention

Choosing antithrombotic regimens for patients with atrial fibrillation (AF) who underwent percutaneous coronary intervention (PCI) with stent placement is challenging. Until recently, the guidelines recommended warfarin-based triple therapy, which causes frequent major bleeding events in up to 12% of patients during the first year of treatment. The WOEST trial, however, revealed that dual therapy, by without aspirin, resulted in significantly lower bleeding risks with similar thromboembolic events to triple therapy. Subsequently, efforts to seek the optimal dual therapy regimens, especially with the combination of a non-vitamin K antagonist oral anticoagulant (NOAC), were initiated. This review highlights the evidence for dual therapy using an NOAC for patients with AF who underwent PCI, with an emphasis on reduced bleeding risk.

The Role of Novel Oral Anticoagulants and Antiplatelet Therapy after Percutaneous Coronary Intervention: Individualizing Therapy to Optimize Outcomes

The number of patients undergoing percutaneous coronary intervention (PCI) who mandate additional oral anticoagulant therapy has been increasing. Dual antiplatelet therapy (DAPT) is associated with reduced ischemic events including stent thrombosis, myocardial infarction and stroke following PCI. However, the tradeoff is an increased risk for bleeding while on DAPT. The addition of a novel oral anticoagulant (NOAC) further increases the likelihood of bleeding while on antiplatelet therapy. Thus, the overall risks and benefits for each patient undergoing PCI on NOAC must be assessed and therapy individualized to ensure optimal therapy for each unique situation. Patients on NOAC undergoing PCI should undergo routine assessment with intravascular imaging as the role of high-risk lesion-related features have increased importance prior to determining optimal duration of treatment with DAPT. We review the best practices for the pharmacologic management of patients requiring anticoagulation with NOAC who are treated with PCI and require antiplatelet therapy.

2018 Korean Heart Rhythm Society Guidelines for Non-Vitamin K Antagonist Oral Anticoagulants / 대한내과학회지

Non-vitamin K antagonist oral anticoagulants (NOACs) are an alternative to vitamin K antagonists (VKAs) and have emerged as the treatment of choice in Korea. However, several questions remain regarding the optimal use of these agents in specific clinical situations. In this paper we discuss 1) patients with atrial fibrillation (AF) and coronary artery disease, 2) avoiding confusion with NOAC dosing across indications, 3) cardioversion in a patient treated with a NOAC, 4) AF patients who present with acute stroke while on NOACs, 5) NOACs in special situations, 6) anticoagulation in AF patients with a malignancy, and 7) optimizing VKA dose adjustments.

Trends and Current Status of Oral Anticoagulant Use in Hospitalized Patients in China / 中国药学杂志

OBJECTIVE: To investigate the trends and current status of oral anticoagulant (OAC) use in hospitalized patients. METHODS: OAC prescriptions of inpatients during 2012 to 2016 were extracted from the database of hospital prescription analysis cooperation program. The extracted prescriptions were restricted to hospitals which located in 5 major cities of China. The number of patients and cost of drugs were calculated and analyzed. RESULTS: A total of 258 276 prescriptions were extracted. The number of patients using OAC increased every year. Warfarin was the most frequently prescribed OAC, but the portion of warfarin decreased. Non vitamin-K antagonist anticoagulants (NOAC) including rivaroxaban increased rapidly. Imbalance existed between warfarin and NOAC on patient population and cost. The use of OAC differed by indications and specialists. CONCLUSION: The number of patients and cost of drugs increased every year while NOAC had taken a large portion of cost. Attention should be payed to the rationality of OAC use.

Label Adherence for Non-Vitamin K Antagonist Oral Anticoagulants in a Prospective Cohort of Asian Patients with Atrial Fibrillation

PURPOSE: Label adherence for non-vitamin K antagonist oral anticoagulants (NOACs) has not been well evaluated in Asian patients with non-valvular atrial fibrillation (AF). The present study aimed to assess label adherence for NOACs in a Korean AF population and to determine risk factors of off-label prescriptions of NOACs. MATERIALS AND METHODS: In this COmparison study of Drugs for symptom control and complication prEvention of AF (CODE-AF) registry, patients with AF who were prescribed NOACs between June 2016 and May 2017 were included. Four NOAC doses were categorized as on- or off-label use according to Korea Food and Drug Regulations. RESULTS: We evaluated 3080 AF patients treated with NOACs (dabigatran 27.2%, rivaroxaban 23.9%, apixaban 36.9%, and edoxaban 12.0%). The mean age was 70.5±9.2 years; 56.0% were men; and the mean CHA₂DS₂-VASc score was 3.3±1.4. Only one-third of the patients (32.7%) was prescribed a standard dose of NOAC. More than one-third of the study population (n=1122, 36.4%) was prescribed an off-label reduced dose of NOAC. Compared to those with an on-label standard dosing, patients with an off-label reduced dose of NOAC were older (≥75 years), women, and had a lower body weight (≤60 kg), renal dysfunction (creatinine clearance ≤50 mL/min), previous stroke, previous bleeding, hypertension, concomitant dronedarone use, and anti-platelet use. CONCLUSION: In real-world practice, more than one-third of patients with NOAC prescriptions received an off-label reduced dose, which could result in an increased risk of stroke. Considering the high risk of stroke in these patients, on-label use of NOAC is recommended.

Quality of Anticoagulation and Treatment Satisfaction in Patients with Non-Valvular Atrial Fibrillation Treated with Vitamin K Antagonist: Result from the KORean Atrial Fibrillation Investigation II

BACKGROUND: Vitamin K antagonist (VKA) to prevent thromboembolism in non-valvular atrial fibrillation (NVAF) patients has limitations such as drug interaction. This study investigated the clinical characteristics of Korean patients treated with VKA for stroke prevention and assessed quality of VKA therapy and treatment satisfaction. METHODS: We conducted a multicenter, prospective, non-interventional study. Patients with CHADS2 ≥ 1 and treated with VKA (started within the last 3 months) were enrolled from April 2013 to March 2014. Demographic and clinical features including risk factors of stroke and VKA treatment information was collected at baseline. Treatment patterns and international normalized ratio (INR) level were evaluated during follow-up. Time in therapeutic range (TTR) > 60% indicated well-controlled INR. Treatment satisfaction on the VKA use was measured by Treatment Satisfaction Questionnaire for Medication (TSQM) after 3 months of follow-up. RESULTS: A total of 877 patients (age, 67; male, 60%) were enrolled and followed up for one year. More than half of patients (56%) had CHADS2 ≥ 2 and 83.6% had CHA2DS2-VASc ≥ 2. A total of 852 patients had one or more INR measurement during their follow-up period. Among those patients, 25.5% discontinued VKA treatment during follow-up. Of all patients, 626 patients (73%) had poor-controlled INR (TTR < 60%) measure. Patients' treatment satisfaction measured with TSQM was 55.6 in global satisfaction domain. CONCLUSION: INR was poorly controlled in Korean NVAF patients treated with VKA. VKA users also showed low treatment satisfaction.

Research progress of oral anticoagulants in patients with liver diseases / 中华肝脏病杂志

Patients with liver disease are at an increased risk of both embolism and bleeding. The optimal anticoagulation strategy remains unclear when associated with venous thromboembolic disease. Moreover, currently approved oral anticoagulant drugs undergo metabolism and elimination in the liver with varying degrees of hepatic dysfunction. Thus, impaired liver function may lead to increased risk of bleeding, making anticoagulant therapy more intricate. This article summarizes the risk of bleeding and thrombosis in patients with liver disease, and the clinical research progress of oral anticoagulants in patients with liver disease to facilitate evidence for choosing oral anticoagulants therapy when required.

Impact of the Health Insurance Coverage Policy on Oral Anticoagulant Prescription among Patients with Atrial Fibrillation in Korea from 2014 to 2016

BACKGROUND: To evaluate oral anticoagulant (OAC) utilization in patients with atrial fibrillation after the changes in the health insurance coverage policy in July 2015. METHODS: We used the Health Insurance Review and Assessment Service-National Patient Samples (HIRA-NPS) between 2014 and 2016. The HIRA-NPS, including approximately 1.4 million individuals, is a stratified random sample of 3% of the entire Korean population using 16 age groups and 2 sex groups. The HIRA-NPS comprises personal and medical information such as surgical or medical treatment provided, diagnoses, age, sex, region of medical institution, and clinician characteristics. The studied drugs included non-vitamin K antagonist OACs (NOACs) such as apixaban, dabigatran, edoxaban, and rivaroxaban, and were compared with warfarin. We analyzed drug utilization pattern under three aspects: person, time, and place. RESULTS: The number of patients with atrial fibrillation who were prescribed OACs was 3,114, 3,954, and 4,828; and the proportions of prescribed NOACs to total OACs were 5.1%, 36.2%, and 60.8% in 2014, 2015, and 2016, respectively. The growth rate of OACs prescription increased from 61.4 patients/quarter before June 2015 to 147.7 patients/quarter thereafter. These changes were predominantly in elderly individuals aged more than 70 years. The proportion of NOACs to OACs showed significant regional difference. CONCLUSION: The change of health insurance coverage policy substantially influenced OACs prescription pattern in whole Korean region. But the impact has been significantly different among regions and age groups, which provides the evidence for developing standard clinical practice guideline on OACs use.

New Anticoagulants for the Prevention and Treatment of Venous Thromboembolism

Anticoagulant drugs, like vitamin K antagonists and heparin, have been the mainstay for the treatment and prevention of venous thromboembolic disease for many years. Although effective if appropriately used, traditional anticoagulants have several limitations such as unpredictable pharmacologic and pharmacokinetic responses and various adverse effects including serious bleeding complications. New oral anticoagulants have recently emerged as an alternative because of their rapid onset/offset of action, predictable linear dose-response relationships and fewer drug interactions. However, they are still associated with problems such as bleeding, lack of reversal agents and standard laboratory monitoring. In an attempt to overcome these drawbacks, key steps of the hemostatic pathway are investigated as targets for anticoagulation. Here we reviewed the traditional and new anticoagulants with respect to their targets in the coagulation cascade, along with their therapeutic advantages and disadvantages. In addition, investigational anticoagulant drugs currently in the development stages were introduced.

The Perioperative Management of Antithrombotic Therapies Using Enoxaparin

Oral anticoagulant therapy is frequently and increasingly prescribed for patients at risk of arterial or venous thromboembolism (VTE). Although elective surgical or invasive procedures have necessitated temporary interruption of anticoagulants, managing these patients has been performed empirically and been poorly investigated. This study was designed to evaluate the adequacy of perioperative anticoagulation using enoxaparin. This was a retrospective, single-center study that evaluated the efficacy and safety of therapeutic-dose enoxaparin for bridging therapy in patients on long-term warfarin at Soonchunhyang University Hospital in Korea between August 2009 and July 2011. Warfarin was discontinued 5 days before surgery, and enoxaparin was administered twice daily by subcutaneous injection at a dose of 1 mg per kg from 3 days before the procedure to the last dose 24 hours before the procedure. Anticoagulation was restarted if proper hemostasis had been confirmed. There were 49 patients, of whom 25 (51%) were men, and the mean age was 63 years. Thirty-four (69%) received warfarin therapy for VTE, and 9 (18%) for atrial fibrillation. Twenty-nine patients (59%) underwent major surgery and 20 (41%) minor surgery. The mean postoperative duration of enoxaparin was 4 days. No patients had thromboembolic complications through 30 days after the procedure. The overall 30-day mortality rate was 0%. In conclusion, our findings demonstrate that bridging therapy with therapeutic-dose enoxaparin is feasible and associated with a low incidence of major bleeding and no thromboembolic complications. However, the optimal approach to managing patients perioperatively is uncertain and requires further evaluation.

Meta-analysis of Efficacy and Safety of Rivaroxaban for Treatment of Deep Venous Thrombosis / 中国药学杂志

OBJECTIVE: To evaluate the efficacy and safety of rivaroxaban in the treatment of deep venous thrombosis(DVT). METHODS: PubMed, Embase, Cochrane Library, Web of Science, Clinical Trials, CNKI, CBM and WANFANG database were systematically searched. All databases had been searched from up to August 2016. All randomized controlled trials (RCTs) of rivaroxaban therapy in patients with deep venous thrombosis were selected. Meta-analysis was carried out by using RevMan 5.3 software. The incidence of recurrent DVT, recurrent VTE, DVT, pulmonary embolism(PE), major bleeding, clinical relevant non-major bleeding(CRNMB) and all-cause mortality after the treatment were compared and the results were presented with risk ratio (RR) with 95% confidence interval (CI). RESULTS: Total 5 RCTs of 4 737 cases were included in this study, including 1 605 cases accepted rivaroxaban (treatment group), other of 3 132 cases accepted other drugs (control group). The results of Meta-analysis were as follows the incidence of recurrent DVT in the rivaroxaban group was lower than that in the unfractionated heparin/low molecular heparin+ vitamin K antagonists (UFH/LMWH+VKA) group (P=0.002). There was no significant difference in the incidence of pulmonary embolism, venous thromboembolism, major bleeding, CRNMB and all-cause mortality between the treatment and control group (P>0.05). CONCLUSION: In the treatment of DVT, rivaroxban shows better efficacy than that of traditional anticoagulant therapy (UFH/LMWH+VKA) and it will not increase the risk of adverse events such as bleeding and death.

A Recurrent Ischemic Stroke Stabilization after Using Non-Vitamin K Antagonist Oral Anticoagulant (NOAC)

Current stroke guidelines recommend the administration of non-vitamin-K-antagonist oral anticoagulant (NOAC) for the prevention of cardioembolic stroke induced by nonvalvular atrial fibrillation. We report a patient who suffered from recurrent posterior circulation strokes-occurring eight times in 4 months-even under adequate antiplatelet medication. Changing the medication from antiplatelet agents to NOAC stopped the stroke recurrence. We suggest that NOAC has a role in the prevention of recurrent stroke of undetermined etiology in the posterior circulation.

Hemothorax due to warfarin overdose / Hemotórax secundário a intoxicação varfarínica

The vitamin K antagonists are the most widely used oral anticoagulant. Although bleedings are common side effect, development of hemothorax is rare. Most cases are associated with impairment in pleura or parenchyma structural alteration in the presence of INR values outside therapeutic range. We report the case of a patient with rheumatoid arthritis presenting with massive hemothorax under anticoagulation with warfarin and present an overview of the main aspects related to warfarin overdose. A 58-year-old woman was evaluated due to transvaginal bleeding and dry cough. In her past medical history, rheumatoid arthritis, smoking and deep venous thrombosis was reported. She had clinical signs of anemia and pulmonary auscultation revealed no lung sounds in the lower third of the right hemithorax. The hemoglobin was 7,2g/dL and the international normalized ratio (INR) was greater than 9. The tomographic study showed pleural effusion and pulmonary embolism in the left pulmonary artery with chronic characteristics, but was negative for pulmonary infarct. The patient received crystalloids, vitamin K and transfusions of blood products. Thoracentesis demonstrated presence of hemothorax. After recovery and hospital discharge, an elective pleural biopsy reveals pleural tissue without histological changes and no signs of malignancy. Despite the fact that hemothorax is a rare complication in patients on oral anticoagulants, this occurrence can be life threatening. The evidence of pleural effusion in these patients should always raise the suspicion of hemothorax. Comorbidities that may affect the lung may be predisposing factors for the occurrence of hemothorax, but the roll of pleural and parenchymal diseases of the lung is not fully clarified and investigation of such conditions should be encouraged.

Os antagonistas da vitamina K são os anticoagulantes orais mais utilizados. Embora sangramentos sejam efeitos colaterais comuns, o desenvolvimento de hemotórax é raro. A maioria dos casos está associada ao comprometimento da pleura ou alteração estrutural do parênquima na presença de valores de INR fora da faixa terapêutica. Relatamos o caso de uma paciente com artrite reumatóide e em anticoagulação com varfarina que apresentou-se com hemotórax maciço. Apresentamos também uma visão geral sobre os principais aspectos relacionados à intoxicação varfarínica. Uma mulher de 58 anos de idade foi avaliada devido a sangramento transvaginal e tosse seca. Em seu histórico médico, artrite reumatóide, tabagismo e trombose venosa profunda foram relatados. Ela tinha sinais clínicos de anemia e a ausculta pulmonar revelou ruídos abolidos no terço inferior do hemitórax direito. A hemoglobina era de 7,2g/dL e a relação normatizada internacional (RNI) maior do que 9. O estudo tomográfico mostrou derrame pleural e embolia na artéria pulmonar esquerda com características crônicas, mas foi negativo para infarto pulmonar. O paciente recebeu cristalóides, vitamina K e transfusões de hemocomponentes. A toracocentese demonstrou presença de hemotórax. Após a recuperação e alta hospitalar, uma biópsia pleural eletiva revelou tecido pleural sem alterações histológicas e sem sinais de malignidade. Apesar do fato de que hemotórax é uma complicação rara em pacientes que tomam anticoagulantes orais, esta ocorrência pode ser fatal. A evidência de derrame pleural nesses pacientes deve sempre levantara suspeita de hemotórax. Co-morbidades que podem afetar o pulmão podem ser fatores predisponentes para a ocorrência de hemotórax, mas o papel de doenças pleurais e parenquimatosas do pulmão não está totalmente esclarecido e a investigação de tais condições deve ser incentivada.

Association Between Usual Vitamin K Intake and Anticoagulation in Patients Under Warfarin Therapy

This study aimed to explore the correlation between usual vitamin K intake and response to anticoagulant therapy among patients under warfarin therapy. We conducted a retrospective survey of patients (n = 50) on continuous warfarin therapy. Clinical information and laboratory parameters were sourced from medical records. Anticoagulant effect was evaluated by using the percent time in therapeutic range (TTR) and the coefficient of variation (CV) of International normalized ratio (INR). Dietary vitamin K intake was assessed using a semi-quantitative food frequency questionnaire that has been developed for the purpose of assessing dietary intake of vitamin K. A total of 50 patients aged between 21 and 87 years were included in the study. The mean vitamin K intake was 262.8 +/- 165.2 microg/day. Study subjects were divided into tertiles according to their usual vitamin K intake. The proportion of men was significantly higher in second and third tertile than first tertile (p = 0.028). The mean percent TTR was 38.4 +/- 28.4% and CV of INR was 31.8 +/- 11.8%. Long-term warfarin therapy group (> or = 3 years) had a higher percentage of TTR as compared to the control group ( 0.05). In conclusion, no significant association was observed between usual vitamin K intake and anticoagulant effects. Further studies are required to consider inter-individual variability of vitamin K intake. Development of assessment tools to measure inter-individual variability of vitamin K intake might be helpful.

Periprocedural antithrombotic management

The periprocedural management of patients on long-term antithrombotic therapy (antiplatelet agents or vitamin K antagonists) who may require temporary disruption, given that an invasive procedure is always a dilemma for clinicians. Discontinuation of antithrombotic therapy can place patients at an increased risk of thromboembolic complications while the continuation of antithrombotic therapy can increase the procedure-related bleeding risk. Therefore, it is imperative for clinicians to be proficient in making thoughtful and individualized decisions on the appropriate management of periprocedural anticoagulants, drawing from recent evidence-based guidelines.