Management of venous thromboembolism in cancer patients and the role of the new oral anticoagulants

Patients with cancer are at high risk for venous thromboembolism (VTE). Most clinical guidelines agree that low-molecular-weight heparins (LMWHs) are the preferred anticoagulants for the prevention and treatment of VTE in cancer patients. However, LMWHs require daily injections, weight-adjustment of dose, and can be associated with heparin-induced thrombocytopenia; all of which are important considerations in managing cancer-associated VTE. Comparatively, the new oral anticoagulants offer a more attractive option because of their oral administration, fixed-dose, and lack of routine laboratory monitoring. The results of phase III trials support the efficacy and safety of the new oral anticoagulants in the management of VTE. However, generalizing these findings to cancer patients with VTE is difficult since very few cancer patients were included. In this comprehensive review, we provide an overview of the current treatment of VTE, explore anticoagulant thromboprophylaxis in ambulatory cancer patients, and summarize existing evidence on the efficacy and safety of the new oral anticoagulants for the management of VTE in both non-cancer and cancer populations.     

Non-vitamin K antagonist oral anticoagulants in elderly patients with atrial fibrillation: A systematic review with meta-analysis and trial sequential analysis

Background: Elderly population is known to be associated with polymedication, comorbidities and altered drug pharmacokinetics. However, the most adequate oral anticoagulant, attending to its relative efficacy and safety, remains unclear.Methods: We searched for phase III randomized controlled trials (MEDLINE, Cochrane Library, SciELO collection and Web of Science) comparing novel non-vitamin K antagonist oral anticoagulants (NOACs) with Vitamin K antagonists (VKA) in the elderly population (≥75 years-old) in atrial fibrillation (AF). Risk ratios (RR) were calculated using a random effects model. Trial sequential analysis (TSA) was performed in statistically significant results to evaluate whether cumulative sample size was powered.Results: Four trials rendered data about elderly (≥75 years-old) and younger patients (<75 years-old) with AF. NOACs demonstrated a 30% significant risk reduction (RR 0.70, 95% CI: 0.61 to 0.80) in elderly patients compared to VKA, without heterogeneity across studies (I² = 0%). The TSA showed that cumulative evidence of this subgroup exceeded the minimum information size required for the risk reduction. In younger patients, VKA and NOACs shared a similar risk of stroke and systemic embolism (RR 0.97, 95% CI: 0.79 to 1.18). Regarding major bleeding risk in the elderly, the overall comparative risk of NOACs was not different from VKA (RR 0.91, 95% CI: 0.72 to 1.16; I² = 86%).Conclusions: NOACs reduce significantly the risk of stroke and systemic embolism in elderly patients without increasing major bleeding events. The dimension of stroke risk reduction was significantly higher in the elderly than in younger adults.     

Place des nouveaux anticoagulants oraux en salle de cardiologie interventionnelle

New oral anticoagulants constitute an important breakthrough for cardiologists and their patients. After reviewing their mechanism of action, their role in the context of interventional cardiology, particularly for patients with acute coronary syndromes, is discussed.     

The Current and Future Role of the Novel Oral Anticoagulants—Indications Beyond Atrial Fibrillation

The direct thrombin inhibitors and Factor-Xa inhibitors are novel oral anticoagulants which are gaining rapid acceptance not only as alternatives to warfarin, but also as recommended first line agents for use as stroke prophylaxis in patients with non-valvular atrial fibrillation.There are, however, other patient settings in which anticoagulation is either indicated or has a potential role. Warfarin is still the predominant anticoagulant used for the treatment and prevention of venous thromboembolic events including deep vein thrombosis and pulmonary embolism as well as in patients with mechanical prosthetic heart valves. In this article, we review the current evidence for the use of dabigatran, rivaroxaban, apixaban and edoxaban in these settings. A summary of suggested regimens utilising these agents is provided. Importantly, in addition, attention is also drawn to clinical scenarios in which use of such agents is considered inappropriate.     

Pharmacology,benefits, unaddressed questions,and pragmatic issues of the newer oral anticoagulants for stroke prophylaxis in non-valvular atrial fibrillation and proposal of a management algorithm

This systematic review aims to provide an update on pharmacology, efficacy and safety of the newer oral direct thrombin and factor Xa inhibitors, which have emerged for the first time in ~ 60 years as cogent alternatives to warfarin for stroke prophylaxis in non-valvular atrial fibrillation. We also discuss on four of the most common clinical scenarios with several unsolved questions and areas of uncertainty that may play a role in physicians' reluctance to prescribe the newer oral anticoagulants such as 1) patients with renal failure; 2) the elderly; 3) patients presenting with atrial fibrillation and acute coronary syndromes and/or undergoing coronary stenting; and 4) patients planning to receive AF ablation with the use of pulmonary vein isolation. New aspects presented in current guidelines are covered and we also propose an evidence-based anticoagulation management algorithm.     

Perioperative venous thromboembolic disease and the emerging role of the novel oral anticoagulants: An analysis of the implications for perioperative management

Venous thromboembolism includes 2 inter-related conditions: Deep venous thrombosis and pulmonary embolism. Heparin and low-molecular-weight heparin followed by oral anticoagulation with vitamin K agonists is the first line and current accepted standard therapy with good efficacy. However, this therapeutic strategy has many limitations including the significant risk of bleeding and drug, food and disease interactions that require frequent monitoring. Dabigatran, rivaroxaban, apixaban, and edoxaban are the novel oral anticoagulants that are available for use in stroke prevention in atrial fibrillation and for the treatment and prevention of venous thromboembolism (HYPERLINK\l ”1). Recent prospective randomized trials comparing the NOACs with warfarin have shown similar efficacy between the treatment strategies but fewer bleeding episodes with the NOACs. This paper presents an evidence-based review describing the efficacy and safety of the new anticoagulants compared to warfarin.     

Emerging options in the treatment of deep vein thrombosis and pulmonary embolism

The incidence of venous thromboembolism (VTE), including deep vein thrombosis and pulmonary embolism, is increasing and the disease has been found to account for over 500,000 annual deaths in the European Union. VTE is associated with increased mortality and may lead to serious long-term complications. Unfractionated heparin (UFH), low molecular weight heparin (LMWH) and vitamin K antagonists (VKA) have remained standard of care for many years. Recent trials of novel anticoagulants have indicated that new therapeutical options may soon become available. Studies on the role of new agents in VTE prevention in patients undergoing orthopaedic surgery have provided the evidence suggesting potential value of these drugs for the management of acute events. At present, investigation of new anticoagulants has reached the stage when phase III clinical studies on some novel agents have been completed and others are in progress. Of those furthest along are the direct Factor Xa inhibitors, rivaroxaban and apixaban, and the direct thrombin inhibitor, dabigatran. Findings of ongoing trials are expected to determine potential impact of these agents on current clinical practice.     

新型抗凝药物防治静脉血栓栓塞症的研究进展

静脉血栓栓塞症(VTE)是由多种遗传性和获得性危险因素共同作用的结果,抗凝治疗是预防和治疗VTE的基础.传统抗凝药物如低分子肝素和华法林防治VTE的有效性已被临床实践充分证实,但其缺点也不容忽视.近年来新型抗凝药物如利伐沙班、阿哌沙班和达比加群等在预防和治疗VTE领域进行了大量临床研究,其安全性与有效性均得到证实,为临床医师治疗VTE提供了更多的选择.     

Incidence, clinical impact and risk of bleeding during oral anticoagulation therapy

Bleeding is the most important complication of oral anticoagulation (OAC) with vitamin K-antagonists. Whilst bleeding is unavoidably related to OAC, it may have a great impact on the prognosis of treated subjects by leading to discontinuation of treatment, permanent disability or death. The yearly incidence of bleeding during OAC is 2%-5% for major bleeding, 0.5%-1% for fatal bleeding, and 0.2%-0.4% for intracranial bleeding. While OAC interruption and/or antagonism, as well as administration of coagulation factors, represent the necessary measures for the management of bleeding, proper stratification of the individual risk of bleeding prior to start OAC is of paramount importance. Several factors, including advanced age, female gender, poor control and higher intensity of OAC, associated diseases and medications, as well as genetic factors, have been proven to be associated with an increased risk of bleeding. Most of these factors have been included in the development of bleeding prediction scores, which should now be used by clinicians when prescribing and monitoring OAC. Owing to the many limitations of OAC, including a narrow therapeutic window, cumber-some management, and wide interand intra-individual variability, novel oral anticoagulants, such as factor Xa inhibitors and direct thrombin inhibitors, have been recently developed. These agents can be given in f ixed doses, have little interaction with foods and drugs, and do not require regular monitoring of anticoagulation. While the novel oral anticoagulants show promise for effective thromboprophylaxis in atrial f ibrillation and venous thromboembolism, def initive data on their safety and eff icacy are awaited.     

Practical Considerations in the Use of Novel Oral Anticoagulants for Stroke Prevention in Nonvalvular Atrial Fibrillation

Atrial fibrillation (AF) is a highly prevalent cardiac arrhythmia associated with an increased risk of stroke. The role of anticoagulation therapy in the prevention of thrombosis and stroke is of critical importance for patients with AF. Limitations with vitamin K antagonists (VKAs), the current standard of care, have led to the development of novel oral anticoagulants (NOACs) that target either thrombin (dabigatran etexilate) or activated factor X (rivaroxaban, apixaban, and edoxaban). In comparison with traditional VKAs such as warfarin, these NOACs offer several pharmacologic advantages, including rapid onset of action, no significant food interactions, low potential for drug–drug interactions, and no requirement for routine coagulation monitoring. Completed phase‐III clinical trials have demonstrated the therapeutic potential of dabigatran, rivaroxaban, and apixaban in comparison with warfarin for stroke prevention in patients with nonvalvular AF (NVAF). While the future utility of NOACs in preventing stroke in patients with NVAF looks promising, several practical issues, including the current lack of a reversal strategy and use of these agents in older patients with renal dysfunction, must be considered. Clinician and patient understanding of such issues will be important for the safe and effective use of NOACs.     

Atrial fibrillation,oral anticoagulants and health related quality of life

IntroductionAtrial fibrillation (AFib) is a disease that can influence the health related quality of life. Also oral anticoagulants can influence it both because of its therapeutic benefits or complications as well as how the anticoagulant usage influence the person's life style by regular laboratory test necessity or diet restrictions.AimDetermine and analyze whether there is a statistically significant difference comparing health related quality of life between K vitamin antagonist, warfarin, users, novel anticoagulant (NOAC), rivaroxaban, dabigatran, users and patients, who do not use any kind of oral anticoagulant.Materials and methodsA cross-sectional analytic research was made in Pauls Stradins Clinical university hospital, Center of Cardiology in Riga, Latvia during the time period from October 2016 till June 2017. Persons with high-risk non-valvular atrial fibrillation were offered to participate in this research. If the person agreed, an oral interview with questions about disease anamnesis, demographic data, laboratory test results, echocardiography results, modified SF-36 survey, used oral anticoagulant type was held. Data were precised with the help of the case anamnesis information. For statistical data analysis was used SPSS Statistics database.ResultsAltogether 218 patients were enrolled, of which 56.9% were female and 43.1% – male, mean age – 70.4 years, mean CHA₂D₂-VASc score – 4.4. Warfarin used 37.6%, 33.0% – novel oral anticoagulants, but 29.4% did not use any kind of oral anticoagulant. A statistically significant difference was discovered between the mean ranks in physical functioning sections comparing warfarin (mean rank 95.85) with NOACs (mean rank 124.57); p = 0.012. Also a statistically significant difference was in social functioning comparing warfarin (mean rank 96.16) with NOACs (mean rank 119.08); p = 0.026. Age had low negative correlation (r = −0.23) with physical functioning. Duration of atrial fibrillation diagnosis did not have correlations with the results.ConclusionNOAC usage correlates with the best health related quality of life scores, gaining a statistically significant difference compared to warfarin users in physical functioning (warfarin – 95.85, NOACs – 124.57; p = 0.012) and social functioning mean ranks (warfarin – 95.16, NOACs – 119.08; p = 0.026). Age had low negative correlation with physical functioning scores.     

Balancing Efficacy and Bleeding Risk in the Prevention of Stroke Due to Atrial Fibrillation with Newer Oral Anticoagulants

With the evaluation and approval of newer oral anticoagulants such as the factor IIa inhibitor, dabigatran etexilate and the factor Xa inhibitors, rivaroxaban and apixaban, strategies for stroke prevention in atrial fibrillation need a thorough re-evaluation of current options. Clinicians are naturally excited about the imminent introduction of these newer drugs that do not need international normalized ratio (INR) monitoring, besides having no drug–food and minimal drug–drug interactions. However, as with all new drugs, it is always prudent to use these judiciously so that they stay in our therapeutic armamentarium for a long time. More than 56 years after the introduction of warfarin we now have three drugs, viz., dabigatran 150 mg bid, rivaroxaban 20 mg od, and apixaban 5 mg bid which were effective in comparison with warfarin in reducing the risk of stroke and bleeding in the landmark trials, RE-LY, ROCKET-AF, and ARISTOTLE respectively. There is a thin dividing line between physiological hemostasis and pathological thrombosis. Routine INR monitoring may not be required but in special situations, such as prior to major surgery, overdose, non-compliance or stroke while on the anticoagulant, one may wish to know whether there are any laboratory measures of efficacy or means of reversal of over anticoagulation. Similar questions may be raised about other situations such as renal dysfunction, cardioversion, ablation procedures, post-stenting, or switch to and from warfarin, heparin or LMWH? This document is an attempt to address these concerns based on available evidence and give physicians a perspective and practice guidelines on how best to use these agents, both old and new, for optimal patient outcomes, maximizing efficacy and minimizing risk.     

Aspirin for prevention and treatment of venous thromboembolism

Venous and arterial thromboses have been regarded for many years as two different diseases requiring anticoagulant or antiplatelet treatment, respectively. Platelets have a role in venous thromboembolism through several mechanisms, including the formation of and adhesion to the neutrophil extracellular traps, as recently demonstrated.