Millions of individuals in the United States require long-term treatment with an oral anticoagulant. For decades, vitamin K antagonists were the only oral option available; however, they have a ...number of well-known limitations. Introduction of the direct oral anticoagulants (DOACs) has long been considered a major therapeutic advance, largely because they lack the need for therapeutic monitoring. Despite this, DOACs, like vitamin K antagonists, can still cause major and clinically relevant nonmajor bleeding, even when used appropriately. Drug-drug interactions (DDIs) involving the DOACs represent an important contributor to increased bleeding risk. Awareness of these DDIs and how best to address them is of critical importance in optimizing management while mitigating bleeding risk. This review provides an overview of DOAC metabolism, the most common drugs likely to contribute to DOAC DDIs, their underlying mechanisms, and how best to address them.
Perioperative management of the bleeding patient Ghadimi, K; Levy, J.H.; Welsby, I.J.
British journal of anaesthesia : BJA,
December 2016, 20161201, 2016-Dec, 2016-12-00, Volume:
117, Issue:
suppl_3
Journal Article
Peer reviewed
Open access
Perioperative bleeding remains a major complication during and after surgery, resulting in increased morbidity and mortality. The principal causes of non-vascular sources of haemostatic perioperative ...bleeding are a preexisting undetected bleeding disorder, the nature of the operation itself, or acquired coagulation abnormalities secondary to haemorrhage, haemodilution, or haemostatic factor consumption. In the bleeding patient, standard therapeutic approaches include allogeneic blood product administration, concomitant pharmacologic agents, and increasing application of purified and recombinant haemostatic factors. Multiple haemostatic changes occur perioperatively after trauma and complex surgical procedures including cardiac surgery and liver transplantation. Novel strategies for both prophylaxis and therapy of perioperative bleeding include tranexamic acid, desmopressin, fibrinogen and prothrombin complex concentrates. Point-of-care patient testing using thromboelastography, rotational thromboelastometry, and platelet function assays has allowed for more detailed assessment of specific targeted therapy for haemostasis. Strategic multimodal management is needed to improve management, reduce allogeneic blood product administration, and minimize associated risks related to transfusion.
The off-label use of direct oral anticoagulants (DOACs) for the treatment of left ventricular thrombi has grown over the past several years given the ease of administration, absence of a requirement ...for international normalized ratio (INR) monitoring, and freedom from dietary restrictions; however, the evidence for their safety and efficacy is contradictory. We systematically searched PubMed and Google Scholar from January 1, 2009, to April 25, 2020, for studies of DOACs for treatment of left ventricular thrombi. Fifty-three articles (of 1,168 patients) met our inclusion criteria. We found that the studies have reached conflicting results; based on our findings, their routine use for the treatment of left ventricular thrombi cannot be recommended. Adequately powered randomized controlled trials are needed to determine the safest and most effective treatment for left ventricular thrombi.
Direct-acting oral anticoagulants (DOACs) are therapeutic alternatives to warfarin that act independently of vitamin K, thus not affecting bone matrix formation. The aim of this study was to compare ...bone mineral density (BMD) and microarchitecture in patients treated with DOACs versus warfarin.
Cross-sectional, observational study in patients using oral anticoagulants for >1 year and a paired control group (CG). Based on the type of anticoagulant used, the patients were grouped into a DOAC (DOACG) or warfarin (WG) group. All patients filled out a questionnaire and underwent BMD evaluation and trabecular bone score (TBS) measurement.
In all, 150 patients were included (50 patients in each group). The mean age was 60.49 ± 7.48 years, and most participants were men (64%). The most frequent comorbidities were hypertension, dyslipidemia, and hyperglycemia (comparison between groups p > 0.05). Low bone mass was diagnosed in 42%, 50%, and 66% of the patients in the CG, DOACG, and WG, respectively (p = 0.012). On logistic regression analysis, BMD was associated with body mass index (BMI; odds ratio OR 0.846, 95% confidence interval CI 0.763–0.926, p = 0.001), creatinine level (OR 0.024, 95%CI 0.001–0.434, p = 0.017), and TBS value (OR 17.777, 95%CI 4.526–96.903, p = 0.000). The mean TBS decreased progressively from the CG to the DOACG and WG (1.328 ± 0.112, 1.264 ± 0.138, and 1.203 ± 0.112, respectively, p < 0.001). On multivariate linear regression, negative predictors of TBS included warfarin use (−0.06, 95%CI -0.11 to −0.02, p = 0.006), BMI (−0.01, 95%CI -0.01 to −0.00, p < 0.001), and hyperglycemia (−0.07, 95%CI -0.11 to −0.03, p = 0.003), while positive predictors were an active IPAQ classification (0.06, 95%CI 0.01–0.11, p = 0.029) and family history of hip fracture (0.07, 95%CI 0.01–0.14, p = 0.029).
Patients using anticoagulants have lower BMD and TBS values compared with controls. This negative effect on bone was more pronounced with warfarin, but was also seen with DOACs.
•Prolonged use of warfarin seems to be a risk factor for osteoporosis.•Direct-acting oral anticoagulants (DOACs) are therapeutic alternatives to warfarin.•Few studies have evaluated the effects of DOACs on bone mass and quality.•Observational study including patients using oral anticoagulants for >1 year.•Oral anticoagulants negatively affect bone density and quality.
Nephrotic syndrome (NS) is one of the common presentations of kidney diseases both in children and adults. NS patients, particularly those with membranous nephropathy, have increased risk of ...thromboembolic events. Heparin and vitamin K antagonists (VKAs) continue to be commonly used as prophylactic and therapeutic agents, given the experience of use of these agents in NS and nonrenal indications of anticoagulation. The use of direct oral anticoagulants (DOACs) in NS is reported in some case series, conference abstracts, and a few small studies. We report our experience of using DOACs in 11 patients of NS with severe hypoalbuminemia. Out of 11, one patient required change of anticoagulation from DOACs to VKA and the rest of them did well with DOACs. There were no bleeding episodes in our study. We suggest larger studies to be carried out to better understand the use of these agents in NS.
Vitamin K antagonists (VKAs), such as warfarin, have been used for thromboprophylaxis and for the treatment of thromboembolic events in patients with nonvalvular atrial fibrillation for over 60 ...years. The increasing use of direct oral anticoagulants (DOACs) in recent years has shown greater advantages and safer use over VKA, including reduced bleeding, fewer drug interactions, no food interactions, a quick onset and offset of activity, and predictable dose-response properties. Despite their advantages, there are a couple of major limitations that raise concerns among clinicians, including the need for more coagulation assays to monitor their effects and more specific reversal antidotes in life-threatening circumstances of bleeding. This review will discuss the important characteristics of the 5 Food and Drug Administration-approved DOACs (including anticoagulation monitoring for each) and the specific and nonspecific reversal agents to DOAC-associated bleeding.
Background The aim of the study was to investigate the specificity of an activated charcoal-based product (DOAC Stop™) initially intended for the specific extraction of direct oral anticoagulants ...(DOACs) from test plasmas on a range of other anticoagulants. Methods Test plasmas were prepared by adding various anticoagulants to pooled normal plasma at concentrations prolonging an activated partial thromboplastin time (APTT) test by a factor of 1.5-3. These plasmas were treated with DOAC Stop™ for 5 and 20 min. Then APTTs were repeated and residual anticoagulant concentrations estimated from dose-response curves. Results The activated charcoal (AC)-based product was found to extract DOACs efficiently. It also bound the intravenous anticoagulants argatroban and lepirudin, but it had no effect on heparin, enoxaparin or danaparoid in plasma. Among other APTT-inhibiting agents that might be present in test plasmas from patients, it extracted protamine, aprotinin and polymyxin. It had no effect on annexin V, thrombomodulin, a typical lupus anticoagulant, a factor VIII antibody, activated protein C or its activator, but it did bind some cationic inhibitors of the APTT with molecular weight below approximately 30 kDa. Conclusions The AC-based product extracted DOACs efficiently with no effect on heparin-type anticoagulants. It did bind argatroban and hirudin-type anticoagulants, which might occur in plasmas from some inpatients, and APTT results obtained after its use should be interpreted after due consideration of patient medications.
Aims
There is no consensus on the haemorrhagic risk associated with potential interactions between commonly used CYP3A4 inhibitors and direct oral anticoagulants (DOACs).
Methods
Macrolide ...antibiotics and azole antimycotics were investigated in this study. Data from Food and Drug Administration Adverse Event Reporting System were retrieved from July 2010 to September 2021. Haemorrhagic signals were expressed by reporting odds ratios (RORs) and 95% confidence intervals (CIs) based on the interaction/noninteraction methodology as (a/c) / (b/d) and considered significant when the lower limit of 95% CI was >1 and the case number of interaction group was ≥3. Subgroup analyses and logistic regression were conducted by adjusting associated factors in haemorrhagic events.
Results
From the third quarter of 2010 to the first quarter of 2021, we retrieved 382 853 distinct cases of adverse events associated with DOACs, in which 1128 cases of bleeding were associated with coadministration of CYP3A4 inhibitors and DOACs. The haemorrhagic signal was significant for apixaban when coadministered with clarithromycin (ROR 1.60, 95% CI 1.16–2.20) and posaconazole (ROR 2.69, 95% CI 1.37–5.28). For dabigatran, coadministration with azithromycin (ROR 4.06, 95% CI 2.77–5.95), fluconazole (ROR 2.26, 95% CI 1.52–3.37), itraconazole (ROR 7.52, 95% CI 1.51–37.46) and ketoconazole (ROR 2.06, 95% CI 1.25–3.41) was associated with significantly higher risks of haemorrhages. At the same time, addition of itraconazole to rivaroxaban also indicated significant haemorrhagic signal (ROR 3.58, 95% CI 1.30–9.85).
Conclusions
Macrolide antibiotics and azole antimycotics have potential but different effects on the bleeding risk of DOACs. Close attention is needed when using these drugs together. Such precautions have already been included in some drug labels.
Direct oral anticoagulants (DOACs) have gained momentum in recent years in patients requiring anticoagulation for the prevention and management of venous thromboembolism and thromboembolic events ...caused by atrial fibrillation. The use of these agents involves potential bleeding complications, particularly during invasive procedures. With increasing use of DOACs, adequate knowledge regarding the perioperative management of patients on DOACs has become indispensable.
This review covers the indications, mechanism of action, and pharmacokinetics of DOACs and their management in different perioperative settings based on various current guidelines and practices. The role of bridging therapy with heparin and the recently developed reversal agents are also discussed.
The perioperative management of DOACs is influenced by drug pharmacokinetics, potential comorbidities of the patient and perioperative thrombotic and bleeding risk. In low bleeding risk and minor procedures, continuing DOACs seems to be safe. Interrupting DOACs in high-risk procedures might be necessary and should be based on the elimination half-life of the drug and renal function of the patient. Further research is needed to better clarify the role of recently developed reversal agents in the perioperative setting and to identify specific laboratory tests to guide the perioperative management of DOACs.
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