vitamin-k-semiquinone-radical and Drug-Related-Side-Effects-and-Adverse-Reactions

Due to the increasing number of patients suffering from cardiovascular diseases, the number of patients started on anticoagulants is also rising. Diet is a modifiable factor of effective treatment. It is of particular importance due to the strong correlation of anticoagulants with vitamin K, other diet components and drug-food interactions in long-term treatment. Chronic treatment with anticoagulants may precipitate a number of adverse reactions, and following an appropriate diet may minimise the side effects of drugs that alter blood coagulation. There is a relationship between diet rich in vitamin K and oral VKAs. Maintaining a constant concentration of vitamin K in everyday diet allows to decrease complications resulting from chronic intake of hydroxycoumarin derivatives. Nutritional education of patients on longterm treatment with VKAs may help to decrease adverse reactions. Collaboration between the patient and the dietician and between the dietician and the doctor may positively affect the maintenance of a stable diet necessary in patients undergoing long-term anticoagulant treatment.

Topics: Anticoagulants; Diet; Drug-Related Side Effects and Adverse Reactions; Food-Drug Interactions; Humans; Vitamin K

Anticoagulant therapy is widely used for prevention and treatment of cardiovascular disease and is frequently prescribed both in primary and secondary care. In comparison to other drugs, the frequency of medication errors is high for anticoagulant therapy. In Denmark, 4,383 adverse events with vitamin K antagonists and 3,234 adverse events with non-vitamin K antagonist oral anticoagulants were reported to the Danish Patient Safety Authority in 2014-2017. In this review, we provide an overview of medication errors and discuss frequent adverse events and pitfalls.

Topics: Administration, Oral; Anticoagulants; Denmark; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Humans; Medication Errors; Patient Transfer; Primary Health Care; Secondary Care; Vitamin K

Low-molecular-weight heparin (LMWH) and vitamin K antagonists (VKA) are current treatment options for cancer patients suffering from acute venous thromboembolism (VTE). The role of direct-acting oral anticoagulants (DOACs) for the treatment of VTE in cancer patients, particular in comparison with the current standard of care which is LMWH, remains unclear. In this network meta-analysis, we compared the relative efficacy and safety of LMWH, VKA, and DOAC for the treatment of cancer-associated VTE.. A pre-specified search protocol identified 10 randomized controlled trials including 3242 cancer patients. Relative risks (RR) of recurrent VTE (efficacy) and major bleeding (safety) were analyzed using a random-effects meta-regression model.. LMWH emerged as significantly superior to VKA with respect to risk reduction of recurrent VTE (RR=0.60, 95%CI:0.45-0.79, p<0.001), and its safety was comparable to VKA (RR=1.08, 95%CI:0.70-1.66, p=0.74). For the DOAC vs. VKA efficacy and safety comparison, the relative risk estimates were in favor of DOAC, but had confidence intervals that still included equivalence (RR for recurrent VTE=0.65, 95%CI:0.38-1.09, p=0.10; RR for major bleeding=0.72, 95%CI:0.39-1.37, p=0.32). In the indirect network comparison between DOAC and LMWH, the results indicated comparable efficacy (RR=1.08, 95%CI:0.59-1.95, p=0.81), and a non-significant relative risk towards improved safety with DOAC (RR=0.67, 95%CI:0.31-1.46, p=0.31). The results prevailed after adjusting for different risk of recurrent VTE and major bleeding between LMWH vs. VKA and DOAC vs. VKA studies.. The efficacy and safety of LMWH and DOACs for the treatment of VTE in cancer patients may be comparable.. Austrian Science Fund (FWF-SFB-54).

Topics: Anticoagulants; Causality; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Female; Hemorrhage; Heparin, Low-Molecular-Weight; Humans; Incidence; Male; Neoplasms; Risk Assessment; Treatment Outcome; Venous Thromboembolism; Vitamin K

The risk of adverse drug reactions (ADRs) rises with increasing age. In the field of ADRs, drug-nutrient interactions (DNIs) are a relatively unexplored area. More knowledge will contribute to the simple prevention of this type of ADR. As the prevalence of vitamin D deficiency in the elderly is high, the primary objective of this review is to evaluate the literature on the relationship between drug use and vitamin D status, focusing on medicines commonly used by the elderly. PubMed was searched for human epidemiological and clinical studies published until early 2013, investigating the relationship between vitamin D blood levels and use of drugs from one of the following groups: proton pump inhibitors (PPIs), biguanides, vitamin K antagonists, platelet aggregation inhibitors, thiazide diuretics, loop diuretics, beta-blocking agents, calcium channel blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-II antagonists, statins, benzodiazepines, and antidepressants. A total of 63 publications were identified. Thiazide diuretics, statins, and calcium channel blocking agents were the most frequently studied drug groups. Associations between thiazides and vitamin D were mixed (n = 22), statins had no or positive associations (n = 16) and calcium blockers were not associated or were negatively associated with vitamin D (n = 10). In conclusion, several knowledge gaps exist on the relationship between drug use and vitamin D blood levels. Available data are scarce (particularly for the aged), study characteristics are highly variable, and found associations may be confounded by, amongst other things, the underlying disease. Nonetheless, this review provides a basis for future research on ADRs that contribute to nutrient deficiencies.

Topics: Aged; Angiotensin-Converting Enzyme Inhibitors; Antidepressive Agents; Calcium Channel Blockers; Diuretics; Drug-Related Side Effects and Adverse Reactions; Humans; Middle Aged; Nutritional Status; Observational Studies as Topic; Platelet Aggregation Inhibitors; Prevalence; Thiazides; Vitamin D; Vitamin D Deficiency; Vitamin K

High-quality anticoagulation management is required to keep these narrow therapeutic index medications as effective and safe as possible. This article focuses on the common important management questions for which, at a minimum, low-quality published evidence is available to guide best practices.. The methods of this guideline follow those described in Methodology for the Development of Antithrombotic Therapy and Prevention of Thrombosis Guidelines: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in this supplement.. Most practical clinical questions regarding the management of anticoagulation, both oral and parenteral, have not been adequately addressed by randomized trials. We found sufficient evidence for summaries of recommendations for 23 questions, of which only two are strong rather than weak recommendations. Strong recommendations include targeting an international normalized ratio of 2.0 to 3.0 for patients on vitamin K antagonist therapy (Grade 1B) and not routinely using pharmacogenetic testing for guiding doses of vitamin K antagonist (Grade 1B). Weak recommendations deal with such issues as loading doses, initiation overlap, monitoring frequency, vitamin K supplementation, patient self-management, weight and renal function adjustment of doses, dosing decision support, drug interactions to avoid, and prevention and management of bleeding complications. We also address anticoagulation management services and intensive patient education.. We offer guidance for many common anticoagulation-related management problems. Most anticoagulation management questions have not been adequately studied.

Topics: Administration, Oral; Decision Support Systems, Clinical; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Fibrinolytic Agents; Fondaparinux; Hemorrhage; Heparin; Humans; Infusions, Intravenous; International Normalized Ratio; Long-Term Care; Patient Education as Topic; Polysaccharides; Randomized Controlled Trials as Topic; Self Care; Societies, Medical; Thrombosis; United States; Vitamin K

Topics: Anticoagulants; Antifibrinolytic Agents; Antithrombins; Biological Availability; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Heparin; Humans; Thrombocytopenia; Thrombosis; Vitamin K

Vitamin K antagonists (VKA) are used for 60 years in the treatment and prevention of thromboembolic disease. VKA were first used as rodenticides. There was a growing use of VKA in humans after President Eisenhower received them after a heart attack in 1955. However, the use of VKA is still challenging because they are characterized by a narrow therapeutic index and a great inter-individual variability in the dose response to the drug. This variability can partly be explained by demographic, clinical and therapeutic factors, but also by genetic variations. The main enzyme responsible for VKA metabolism is the hepatic cytochrome P450 2C9 (CYP2C9). Vitamin K epoxide reductase complex subunit I (VKORC1) is a key enzyme in the vitamin K cycle and was identified as the pharmacological target of VKA. Genetic variations affecting both CYP2C9 and VKORC1 are associated with a significant decrease in the VKA dose requirements and an increased risk of bleeding. Genotyping both CYP2C9 and VKORC1 before the initiation of VKA allows to identify a subgroup of patients with an early response to VKA therapy, that expose them to overdosage and a higher bleeding risk. More recently, a polymorphism in the gene encoding CYP4F2 has been identified and may partly explain the variability in warfarin maintenance dose by altering the metabolism of vitamin K. In addition, rare mutations have been found in VKORC1 that could explain very high VKA dose requirements and pharmacodynamic resistance.

Topics: Anticoagulants; Drug Discovery; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Humans; Models, Biological; Pharmacogenetics; Polymorphism, Genetic; Public Health; Thromboembolism; Vitamin K; Warfarin

Anticoagulants are effective in the prevention and treatment of a variety of arterial and venous thrombotic disorders but are associated with an increased risk of serious bleeding complications. Based on well documented studies of patients using vitamin K antagonists the incidence of major bleeding is 0.5%/year and the incidence of intracranial bleeding is 0.2%/year, however, in real life practice this incidence may be even higher. Risk factors for bleeding are the intensity of anticoagulation, the management strategy to keep the anticoagulant effect in the desired range, and patient characteristics. Recently, a new generation of anticoagulants have been developed and is currently evaluated in clinical trials. Initial results show a similar or superior efficacy over conventional anticoagulant agents with a good safety profile. In case of serious bleeding complications in a patient who uses vitamin K antagonists, this anticoagulant treatment can be quickly reversed by administration of vitamin K or coagulation factor concentrates. For the newer anticoagulants, quick reversal strategies are more cumbersome, although some interventions, including prothrombin complex concentrates, show promising results in initial experimental studies.

Topics: Anticoagulants; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Prevalence; Risk Assessment; Risk Management; Thromboembolism; Vitamin K

Anticoagulation with vitamin K antagonists (VKAs) is effective in the prevention and treatment of thrombotic complications in many clinical conditions, including atrial fibrillation (that represents today the most frequent indication for anticoagulant treatment), venous thromboembolism, acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients, limiting a more widespread prescription of the treatment. As a result, a non negligible proportion of all the subjects who would have a clear clinical indication for anticoagulation do not receive an effective treatment. This review analyses the treatment- and person-associated risk factors for bleeding during VKAs. New oral anticoagulant drugs seems to overcome at least some of the limitations of VKAs. Potentially, they can allow a less demanding and more stable anticoagulant treatment, with less side-effects allowing that more patients can receive an appropriate anticoagulant treatment. Based on the so far available phase III clinical studies, it is possible to assume that these new drugs are associated with a risk of bleeding, that is probably related to the intensity of treatment.

Topics: Age Distribution; Anticoagulants; Comorbidity; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Prevalence; Risk Assessment; Risk Management; Sex Distribution; Survival Analysis; Survival Rate; Thromboembolism; Vitamin K

Prevention of atrial fibrillation-related stroke is an important part of atrial fibrillation management. However, stroke risk is not homogeneous and varies with associated morbidities and risk factors. Risk stratification schemes have been developed that categorize patients' stroke risk into classes based on a combination of risk factors. According to the calculated level of risk, guidelines recommend patients with atrial fibrillation receive antithrombotic therapy either as a vitamin K antagonist or aspirin. Despite recommendations, however, many patients with atrial fibrillation do not receive adequate thromboprophylaxis. We will discuss some of the underlying reasons, in part related to the drawbacks associated with vitamin K antagonists. These highlight the need for new anticoagulants in atrial fibrillation. The novel oral anticoagulants in development may overcome some of the limitations of vitamin K antagonists and address their underuse and safety concerns.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antithrombins; Aspirin; Atrial Fibrillation; Contraindications; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Drugs, Investigational; Factor Xa Inhibitors; Fibrinolytic Agents; Guideline Adherence; Humans; Randomized Controlled Trials as Topic; Risk Factors; Stroke; Vitamin K

Disorders of coagulation are common adverse drug events encountered in critically ill patients and present a serious concern for intensive care unit (ICU) clinicians. Dosing strategies for medications used in the ICU are typically developed for use in noncritically ill patients and, therefore, do not account for the altered pharmacokinetic and pharmacodynamic properties encountered in the critically ill as well as the increased potential for drug-drug interactions, given the far greater number of medications ordered. This substantially increases the risk for coagulation-related adverse reactions, such as a bleeding or prothrombotic events. Although many medications used in the ICU have the potential to cause coagulation disorders, the exact incidence will vary based on the specific medication, dose, concomitant drug therapy, ICU setting, and patient-specific comorbidities. Clinicians must strongly consider these factors when evaluating the risk/benefit ratio for a particular therapy. This review surveys recent literature documenting the risk for adverse drug reactions specific to bleeding and/or clotting with commonly used medications in the ICU.

Topics: Anti-Infective Agents; Anticoagulants; Antifibrinolytic Agents; Blood Coagulation Disorders; Blood Coagulation Factors; Colloids; Critical Care; Deamino Arginine Vasopressin; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Estrogens, Conjugated (USP); Factor VIIa; Fibrinolytic Agents; Fondaparinux; Hemostatics; Humans; Polysaccharides; Protein C; Recombinant Proteins; Thrombin; Thromboembolism; Vitamin K

Recombinant factor VIIa has been increasingly used to provide hemostasis in nonapproved indications. This trend has resulted in concerns about safety, efficacy and costs.. Recombinant factor VIIa seems to have hemostatic effects in posttrauma and perisurgery excessive bleeding, although further studies are required. Recombinant factor VIIa may be used to reverse the effect of warfarin or other vitamin K-antagonist therapy following vitamin K administration. Some beneficial effects have also been suggested in a limited number of patients with liver disease and hemorrhagic stroke. Recombinant factor VIIa should be used with caution in cases with known hypercoagulability, excessive bleeding in the setting of disseminated intravascular coagulation or other states of generalized activation of the hemostatic system. In most of the nonapproved cases, a 4.8-mg vial administered to an adult patient weighing 50-100 kg to achieve a 50-100 microg/kg dose is recommended.. While consensus recommendations on the use of recombinant factor VIIa in nonapproved settings have been developed, more studies are needed to define dose and timing in these diverse patient populations. For now, decisions about off-label use of recombinant factor VIIa remain at the physician's discretion, assisted by hospital pharmacotherapeutic or transfusion committees.

Topics: Adult; Consensus; Disseminated Intravascular Coagulation; Drug Antagonism; Drug-Related Side Effects and Adverse Reactions; Factor VIIa; Hemostasis; Hospitals; Humans; Pharmacy and Therapeutics Committee; Recombinant Proteins; Stroke; Vitamin K; Warfarin

The number of patients anticoagulated with warfarin has rapidly increased over the last decade. Approximately 1% of these patients experience serious bleeding and 0.5% die annually from bleeding. The management of hemorrhage in the overanticoagulated patient is complex and is based on balancing the risks and benefits of each therapeutic intervention. For life-threatening bleeding, the use of clotting factor concentrates is essential for immediate anticoagulation reversal, whereas for less severe bleeding intravenous vitamin K is the treatment of choice. Vitamin K (by the intravenous or oral route) should also be used in overanticoagulated patients who are not actively bleeding but who are at high risk of doing so if their anticoagulation is not, at least partially, corrected.

Topics: Anticoagulants; Blood Coagulation Factors; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Plasma; Risk; Vitamin K; Warfarin

Topics: Anticoagulants; Chloramphenicol; Clofibrate; Contraceptives, Oral; Coumarins; Diuretics; Drug Interactions; Drug Synergism; Drug-Related Side Effects and Adverse Reactions; Estrogens; Ethanol; Heparin; Humans; Hypnotics and Sedatives; Phenylbutazone; Phenytoin; Salicylates; Thyroxine; Tolbutamide; Vitamin K

Peri-procedural management of warfarin reflects an intricate balance between the restoration of haemostasis and appropriate thromboprophylaxis. This prospective single-arm study assessed the safety and efficacy of a convenient schedule, incorporating low-dose intravenous vitamin K (vitK(IV) ) for short-term warfarin reversal prior to elective surgery, as well as vitK-dependent factor levels (vitK-Factors) and International Normalized Ratio (INR) pre- and post-vitK(IV) . One seventy eight patients on long-term warfarin received 3mg vitK(IV) 12-18 h pre-procedure with no adverse reactions. 167/178 (94%) achieved an INR≤1·5 post-vitK(IV) on the day of surgery, while all achieved INR≤1·7. Four patients had procedure-associated major bleeding, but importantly had achieved a pre-procedure INR<1·5 and vitK-Factors >0·30iu/ml. No patient suffered a symptomatic thromboembolism during the 6-week follow-up. Median days to re-establish a therapeutic INR were 4 (range 2-11). VitK(IV) near normalized all vitK-Factors, with a uniform pattern of depletion and repletion in association with an increase and decrease in INR, respectively; and from the data, INR<1·5 correlated with vitK-Factors >0·30iu/ml. Low-dose vitK(IV) for short-term warfarin reversal was reliable and safe, and successfully lowered the INR to an acceptable level for planned surgery, with no excess of bleeding, thromboembolism, delayed discharge, or resistance to warfarin. The protocol was simple and convenient for both the patients and the healthcare institution.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Loss, Surgical; Drug-Related Side Effects and Adverse Reactions; Elective Surgical Procedures; Female; Humans; International Normalized Ratio; Male; Middle Aged; Perioperative Care; Premedication; Preoperative Care; Treatment Outcome; Vitamin K; Warfarin

Topics: Bone Marrow Transplantation; Drug-Related Side Effects and Adverse Reactions; Humans; Vitamin K; Vitamin K Deficiency

Our aim was to compare adverse drug reactions (ADRs) associated with direct-acting oral anticoagulants and vitamin K antagonists from the European EudraVigilance (EV) database. The EV database is the system for the analysis of information on suspected ADRs that are authorised, or being evaluated in clinical trials, in the European Economic Area. Registered ADRs (from the groups "Gastrointestinal disorders", "General disorders and administration site conditions", "Injury, poisoning and procedural complications", "Nervous system (NS) disorders" and "Vascular disorders") for apixaban, rivaroxaban, dabigatran and vitamin K antagonists (VKA) were collected by age group (< 65 years; 65-85 years and > 85 years) and by sex. The proportional reporting ratio (PRR) was used to compare ADRs in relation to the anticoagulants tested. A total of 274,693 ADRs were analysed. For gastrointestinal ADRs, patients treated with rivaroxaban and dabigatran (PRR 2.17 and 2.51, respectively) were at significantly higher risks than those treated with apixaban and VKA (PRR 1.27 and 1.47, respectively), while risks for vascular disorders were increased by all anticoagulants that were tested. Lastly, none of the anticoagulants significantly increased the risk of ADRs within the NS group. Rivaroxaban and dabigatran were associated with a significantly higher risk of gastrointestinal ADR than apixaban or VKA. All anticoagulants increased the risk of vascular pathology while none of them demonstrated significant increased risk of ADR to NS.

Topics: Administration, Oral; Adolescent; Adult; Aged; Aged, 80 and over; Anticoagulants; Dabigatran; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Diseases; Humans; Male; Middle Aged; Pharmacovigilance; Pyrazoles; Pyridones; Rivaroxaban; Vitamin K; Young Adult

Oral anticoagulants, including vitamin K inhibitors (VKAs) and direct anticoagulants (DOACs) are important for preventing and treating thromboembolic diseases. However, they are not recommended for use in all patients due to negative side effects and adverse drug reactions (ADRs). Currently, there is a paucity of information about their use in real life. Therefore, the aim of this pilot study is to report on the rate of serious ADRs in oral anticoagulant users, determine patient characteristics associated with increased risk of ADRs, and identify possible management strategies for reducing risk of ADRs within a hospital setting.. Patients admitted to the Internal Medicine Department of the Vimercate Hospital were recruited between November 1, 2015 and October 31, 2016. All patients reporting an ADR associated with anticoagulant use were selected. Demographic, clinical, and observational data were extracted from electronic hospital records, in particular, by the hospital discharge letters and other clinical records. The main outcome of the study was to evaluate the incidence of anticoagulants serious adverse drug reactions conditioning hospital admission, the percentage of preventable reactions, and the determinants of those.. Of the 2,064 admissions, 102 (4.9%) eligible patients were identified. Age ranged from 60-95 years (mean = 81.9, standard deviation = 6,59) and 47.1% (n=48) were female. Of the 102 cases, 68 used VKAs and 34 used DOACs. The most common admission diagnosis was heart failure following anemia or hemorrhage (56 cases), followed by acute hemorrhage (with or without anemia; 29 cases), and anemia not associated with evident hemorrhage (17cases). The majority of VKA users (n=65, 95.6%) had a high risk of major bleeding. ADRs were found to be preventable in 96% of VKA users and 68% of DOACs users.. This study highlights the large percentage of ADRs from oral anticoagulants that can be avoided with more careful patient management. Periodic check-up of cardiac and renal function, as well as blood count, may be useful for reducing the risk of ADRs, especially in older DOACs users. Further research is needed to get new data to improve the patients monitoring system.

Topics: Aged; Aged, 80 and over; Anemia; Anticoagulants; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Hospital Records; Hospitalization; Humans; Male; Middle Aged; Monitoring, Physiologic; Vitamin K

Although dabigatran has a favorable risk-benefit profile compared with vitamin K antagonist therapy for venous thromboembolism and nonvalvular atrial fibrillation, major bleeding events, including gastrointestinal (GI) bleeding, may occur. Therefore, our aim was to provide insights into the efficacy and safety of idarucizumab for urgent dabigatran reversal in patients with major GI bleeding.. Patients with uncontrollable GI bleeding requiring reversal were enrolled from June 2014 through July 2016 in the RE-VERSE AD study (Reversal of Dabigatran Anticoagulant Effect With Idarucizumab), a prospective, multicenter, open-label study of idarucizumab, and were followed up for 90 days for primary and secondary outcomes. Patients were to receive a 5-g dose of intravenous idarucizumab, administered as 2 bolus infusions of 2.5 g no more than 15 minutes apart. The primary end point was the maximum reversal of dabigatran anticoagulation within 4 hours after administration of idarucizumab as measured by the dabigatran-specific assays diluted thrombin time and ecarin clotting time. Further end points included investigator-reported bleeding cessation within the first 24 hours and incidence of rebleeding, thromboembolic events, or mortality.. GI bleeding occurred in 137 patients enrolled in RE-VERSE AD, of which 84% was adjudicated as major or life-threatening, 48 (35.0%) was upper GI tract in origin, 43 (31.4%) was lower GI in origin, and 46 (33.6%) was either both or unknown. Complete reversal of dabigatran was observed in 118 of 121 patients (97.5%) with an elevated diluted thrombin time at presentation and 95 of 131 patients (72.5%) with an elevated ecarin clotting time and was similar for upper and lower GI bleeding. Bleeding cessation within 24 hours was reported in 92 of 134 evaluable patients (68.7%) after a median duration of 2.4 hours (interquartile range, 2.0-3.9 hours). During the 90-day follow-up, 6 patients (4.4%) had a postreversal thromboembolic event, and 20 patients (14.6%) died.. Idarucizumab showed a rapid and complete reversal of dabigatran activity in nearly all patients presenting with GI bleeding, facilitating emergency patient care without the additional presence of anticoagulation.. URL: https://www.clinicaltrials.gov . Unique identifier: NCT02104947.

Topics: Aged; Aged, 80 and over; Antibodies, Monoclonal, Humanized; Anticoagulants; Dabigatran; Drug Substitution; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Gastrointestinal Hemorrhage; Humans; Male; Middle Aged; Prospective Studies; Risk Assessment; United States; Venous Thromboembolism; Vitamin K

Patients with atrial fibrillation generally require anticoagulant therapy and, at times, therapy with additional platelet aggregation inhibitors. Data are scarce on bleeding rates in high-risk groups receiving combination therapy, such as the elderly or patients with a high CHA. We conducted a nationwide cohort study of Danish patients with atrial fibrillation ≥50 years of age. Treatments were ascertained from a prescription database. These included no anticoagulant treatment, and treatment with vitamin K antagonists, direct oral anticoagulants, platelet inhibitors, and combinations of antithrombotic drugs. Incidence rates (IRs) of major bleeding and hazard ratios were estimated overall, and also stratified by treatment modality, age, CHA. Patients with atrial fibrillation on triple therapy experienced high rates of major bleeding in comparison with patients on dual therapy or monotherapy. The high bleeding rates observed in patients on triple therapy >90 years of age or with a CHA

Topics: Aged; Aged, 80 and over; Atrial Fibrillation; Databases, Factual; Denmark; Disease Progression; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Fibrinolytic Agents; Follow-Up Studies; Hemorrhage; Humans; Male; Platelet Aggregation Inhibitors; Treatment Outcome; Vitamin K

Knowledge on adverse effects (AEs) related to non-vitamin K antagonist oral anticoagulants (NOACs) in real-world populations is sparse.. Our objective was to identify signals of potential AEs in patients with atrial fibrillation (AF) initiating NOAC treatment using a hypothesis-free screening approach.. Using the nationwide Danish registries, we identified patients with AF initiating dabigatran, rivaroxaban, or apixaban between 2011 and 2015 (n = 50,627). Applying a symmetry analysis design, we screened for AEs of NOAC, as reflected by new drug treatments, incident diagnoses, or procedures. For signals with the lowest number needed for one additional patient to be harmed (NNTH), we evaluated whether they likely represented genuine AEs or other types of associations. Signals assessed as potential AEs were grouped into five categories for analysis of effect modification according to patient and drug characteristics.. Of the identified signals, 61 were classified as potential AEs. Most signals could be categorized as the following types of AEs: bleedings, non-bleeding gastrointestinal symptoms, mental disease, urinary tract disorders, and musculoskeletal symptoms. Older age and first-ever use of anticoagulants was associated with strengthening of all "NOAC-adverse effect" associations. Conversely, use of low-dose NOAC and apixaban led to attenuation of most associations.. Through a symmetry analysis-based hypothesis-free screening of large-scale healthcare databases, we were able to confirm well-established AEs of NOAC therapy in clinical practice as well as potential AEs that deserve further investigation.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Denmark; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Middle Aged; Registries; Vitamin K

Isolated arthralgia, without hemorrhagic side effect, exists and is considered as a very rare adverse drug reaction according to vitamin K antagonists' (VKAs) summary of product characteristics. Up to now, there are no literature reports of isolated, nonhemorrhagic joint complications in patients receiving VKAs. Hence, the objective of this study was to describe cases of VKA-related nonhemorrhagic joint disorders (fluindione, warfarin, and acenocoumarol) reported in the French Pharmacovigilance Database (FPVD). Sixty-one reports (male : female ratio, 1.18; median [interquartile range (IQR)] age: 60 [49-72]) were found. Fluindione, warfarin, and acenocoumarol were respectively suspected in 42, 12, and 7 cases. Arthralgia was reported in 47 cases (77%), arthritis in nine cases (15%), capsulitis in three cases (5%), and bursitis in two cases (3%). Although the joint symptoms mainly concerned the lower limbs, all types of joints were affected. Arthralgia was associated with myalgia in 14 cases and with tendinitis in three cases. The median (IQR) time interval between VKA introduction and arthralgia onset was 26 (10-98) days (range: 1-6935). VKA was withdrawn in 44 cases, and a decrease in the intensity of joint symptoms was observed in 30 cases. In three cases, reintroduction of the same VKA led to the recurrence of symptoms. In view of the large prescription of this drug class worldwide, patients and clinicians (and especially primary care physicians and geriatricians) should be aware of this possible adverse drug reaction when confronted with joint disorders in patients of all ages taking VKAs.

Topics: Acenocoumarol; Aged; Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Joint Diseases; Male; Middle Aged; Pharmacovigilance; Phenindione; Vitamin K; Warfarin

Adverse events related to vitamin K antagonists (VKA) represent a major public health problem. Informative tools and educative program contributes to the reduction of iatrogenic risk. The purpose of our study is to assess representations and information needs of patients under VKA therapy in order to develop a suitable therapeutic education program.. Individual semi-structured interviews were conducted among both long term VKA therapy patient and patients initiating VKA. The thematic analysis allowed us to explore patient's speech qualitatively and semi-quantitatively.. The main needs in information concerned the modalities of treatment (27.6%), side effects (24.1%), precautions and management of VKA treatment (24.1%). Origin of the disease (P=0.022) and drug mechanism of action (0.012) were specially asked about by patients initiating their treatment.. Patients under VKA therapy reported needs for information on both their pathology and their anticoagulant therapy. The therapeutic education approach will enable us to adapt the educational tools and messages to the needs of patients under VKA therapy.

Topics: 4-Hydroxycoumarins; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Disorders; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Indenes; Information Dissemination; Male; Middle Aged; Needs Assessment; Patient Education as Topic; Patient Preference; Vitamin K

Vitamin K antagonists (VKA) are currently the most prescribed oral anticoagulant treatment in Tunisia. Despite the standardization of biological monitoring and the better definition of therapeutic objectives, their side effects are a frequent reason for hospitalization.. To evaluate patients' knowledge about their VKA treatment.. We realized a cross-sectional descriptive study in the Cardiology Department of HabibThameur Hospital from September to October 2016. A questionnaire consisting of 14 items was used in a semi-directed interview in order to assess patients' knowledge on their VKA treatment.. Our study included one hundred patients. Mean age was 61 ± 12 years and sex ratio of 1.8. Forty-eight per cent were illiterate. The median duration of AVK intake was 5 years. Atrial fibrillation (AF) was the most frequent indication (57%). Eighty percent of patients had more than five correct answers on the eight items of knowledge: VKA's name (96%), tablet description (93%), dose (99%), time (94%), VKA's effect (70%), INR (56%), treatment's risk (49%) and the target INR (20%). Twenty-two percent had more than four correct answers on the 6 items of know-how: what to do in case of haemorrhage (70%), what to do in case of oblivion (45%), interactions precautions to be observed with food (13%), activities advised against (49%) and medical procedures advised against (27%). In multivariate analysis, only prior VKA information was significantly associated with a better knowledge of VKA (p = 0.027).. Our patients' knowledge on their VKA treatment was insufficient to ensure the safety and efficacy of treatment. The creation of a therapeutic education program on is therefore necessary to reduce the iatrogenic risk of this treatment.

Topics: 4-Hydroxycoumarins; Adult; Aged; Aged, 80 and over; Anticoagulants; Attitude to Health; Blood Coagulation Disorders; Cross-Sectional Studies; Drug-Related Side Effects and Adverse Reactions; Educational Status; Female; Health Knowledge, Attitudes, Practice; Hemorrhage; Hospitalization; Humans; Indenes; Knowledge; Male; Middle Aged; Surveys and Questionnaires; Vitamin K

Management of vitamin K antagonists (VKAs) is difficult, and overdoses can have dramatic hemorrhagic consequences. The adverse drug event (ADE) scorecards is a tool intended for the detection and description of adverse drug reaction/ADE developed during a European computerized medical data processing project. It is used in a quality assurance process. Our objective was to evaluate the performance of the ADE scorecards in the detection of the contributing factors for VKA overdoses, among the cases where a VKA overdose is observed.. Twenty-eight rules allow the detection of VKA treatment overdose related to drug or a clinical situation. They were applied on 14,748 electronic medical records from a community hospital. Among 582 records including a VKA prescription, 59 cases of VKA overdoses (international normalized ratio ≥ 5) during the hospital stay have been identified. The ADE scorecards detected 49 of them. We evaluated the positive predictive value and sensitivity of these rules, by an expert review of the cases.. The expert review confirmed the contribution of a detected risk factor to the VKA overdose in 11 cases. Therefore, the precision of the rules is 22.4%. The sensitivity is 84.6%. The risk factors were mainly infection and amiodarone introduction. The 4 cases of clinical injury related to a drug were properly designated by the rules.. Our study shows the great potential of the ADE scorecards for detecting cofactors of VKA overdoses and gives an argument to include complex rules in the knowledge bases used for the detection and identification of ADEs in large medical databases.

Topics: Anticoagulants; Clinical Audit; Drug-Related Side Effects and Adverse Reactions; Electronic Health Records; Hemorrhage; Humans; Middle Aged; Retrospective Studies; Risk Factors; Software; Vitamin K

The public health relevance of drug-nutrition interactions is currently highly undervalued and overlooked. This is particularly the case for elderly persons where multi-morbidity and consequently polypharmacy is very common. Vitamins and other micronutrients have central functions in metabolism, and their interactions with drugs may result in clinically relevant physiological impairments but possibly also in positive effects. On 12 April 2016, the University Medical Center Groningen (The Netherlands), as part of its Healthy Ageing program, organized a workshop on the public health relevance of drug-nutrient interactions. In this meeting, experts in the field presented results from recent studies on interactions between pharmaceuticals and nutrients, and discussed the role of nutrition for elderly, focusing on those persons receiving pharmaceutical treatment. This paper summarizes the proceedings of the symposium and provides an outlook for future research needs and public health measures. Since food, pharma and health are closely interconnected domains, awareness is needed in the medical community about the potential relevance of drug-nutrition interactions. Experts and stakeholders should advocate for the integration of drug-nutrition evaluations in the drug development process. Strategies for the individual patients should be developed, by installing drug review protocols, screening for malnutrition and integrating this topic into the general medical advice.

Topics: Contraceptives, Oral; Drug-Related Side Effects and Adverse Reactions; Fatty Acids, Omega-3; Female; Folic Acid; Food-Drug Interactions; Gastrointestinal Microbiome; Humans; Male; Meta-Analysis as Topic; Micronutrients; Netherlands; Nutritional Status; Public Health; Vitamin D; Vitamin K

Vitamin K antagonists (VKA) are used by 1,7% of the French population. Patient education and monitoring can decrease the number of iatrogenic hospitalizations due to VKA. We assessed the impact of a communication between hospital and retail pharmacists about patient's knowledge on VKA. The aim of our study has been to evaluate the value added by the link between the hospital pharmacist and the community pharmacist on the follow-up of patients treated by vitamin K antagonist. Patient information about VKA treatment is offered to inpatients in our hospital. An information form is filled for each patient treated by VKA. Patient's knowledge is assessed on the document (Name of VKA, cause of treatment, monitoring, risks of overdose, compliance…). This form is sent to the community pharmacist after the training when the patient leaves the hospital (by fax or by email). The form is sent back by the community pharmacist after the second training. Sixty-eight patients received the training, 48 forms have been sent to the retail pharmacists and 43 forms have been sent back to the hospital. Seven retail pharmacists replied spontaneously. Twenty-eight patients increased their knowledge (in average+21%) and 12 patients stabilized their knowledge. The best-known concepts were the INR target, the time of drug intake, the risks of overdose and the information of the family. The improvement of knowledge is significant for the name of VKA, the cause of treatment, efficacy assessment and signs of overdose. The implementation of a communication between the hospital and the retail pharmacies is time-consuming but the follow-up of those patients seems essential to keep a good knowledge.

Topics: Aged; Aged, 80 and over; Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; France; Humans; Male; Middle Aged; Patient Education as Topic; Pharmacies; Pharmacy Service, Hospital; Vitamin K

A four-factor prothrombin complex concentrate (4F-PCC) was recently licensed in the United States for urgent vitamin K antagonist (VKA) reversal based on two randomized clinical trials. These studies excluded patients at high risk of thrombosis; therefore, the risk of thrombotic complications in unselected patients remains a concern.. This study retrospectively evaluated the incidence of thromboembolic events (TEEs) and death in patients who received 4F-PCC for VKA reversal. The study included 113 consecutive patients who were 18 years of age and older and were administered 4F-PCC for VKA reversal. The incidence of TEE and deaths was evaluated for up to 60 days after PCC administration or until the end of hospitalization, whichever came later.. Seven (6.2%) patients developed TEEs and 17 (15%) patients died. PCC administration was probably related to TEE and subsequent death in two (1.8%) patients. Multivariate analysis revealed that a diagnosis of Factor V Leiden or antiphospholipid syndrome was predictive of TEE, and active malignancy was predictive of death.. This study supports the safety of 4F-PCC for urgent VKA reversal even in unselected patients. The underlying type of hypercoagulable state and the dose of PCC may influence the incidence of TEE.

Topics: 4-Hydroxycoumarins; Adult; Aged; Aged, 80 and over; Anticoagulants; Blood Coagulation Factors; Drug-Related Side Effects and Adverse Reactions; Female; Hospitals, Teaching; Humans; Incidence; Indenes; Male; Middle Aged; Professional Practice; Retrospective Studies; Texas; Thromboembolism; Treatment Outcome; Vitamin K

Topics: Anticoagulants; Dabigatran; Dose-Response Relationship, Drug; Drug Monitoring; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Pyrazoles; Pyridones; Reference Standards; Risk Factors; Rivaroxaban; Vitamin K

Several drug classes are known to be associated with serious upper gastrointestinal bleeding (UGIB), among others NSAID, low-dose acetylsalicylic acid (ASA), vitamin K antagonists (VKA), clopidogrel and selective serotonin reuptake inhibitors (SSRIs). There are few data on how and to what extent these drugs are reintroduced in patients who have been discharged after a bleeding episode related to any of them.. To assess if physicians re-prescribed potential causative drugs after an episode of UGIB and to explore whether drugs with antihaemostatic action (DAHA) are re-prescribed without a gastro-protective agent.. By use of the Kaplan-Meyer method, we estimated the time from UGIB to re-prescribing for 3652 cases who were all admitted to hospital with a diagnosis of serious upper gastrointestinal bleeding from 1995 to 2006. Data on drug exposure were retrieved from a Danish prescription database, a recent study on drug-related UGIB, and The National Board of Health in Denmark.. One-year rates of re-prescribing after UGIB were; 82%, 25%, 43%, 68%, 55%, 71% for SSRIs, NSAID, low-dose ASA, VKA, clopidogrel and dipyridamol, respectively. However, re-prescribing rates without proton pump inhibitors (PPIs) were markedly lower 25%, 3%, 5%, 1%, 17% and 6%, respectively. Non-users of DAHA had a prevalence of PPI use of about 30% a few months after an UGIB.. Drugs with antihaemostatic action are re-prescribed to a large extent after an episode of upper gastrointestinal bleeding, but usually covered by PPIs. This use of PPI is specific for users of drugs with antihaemostatic action.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Case-Control Studies; Drug Prescriptions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Gastrointestinal Hemorrhage; Hematologic Agents; Humans; Middle Aged; Patient Discharge; Practice Patterns, Physicians'; Proton Pump Inhibitors; Risk Factors; Selective Serotonin Reuptake Inhibitors; Time Factors; Vitamin K

Not all clinicians give vitamin K to severe malaria patients with systemic bleeding. Vitamin K injections may not be useful to stop bleeding in severe malaria patients with predominant hepatocellular jaundice. However, vitamin K may be justified in bleeding patients who have prolonged fasting of more than 3-7 days, underlying malnutrition, or predominant cholestatic jaundice. The decision to give vitamin K to severe malaria patients with systemic bleeding should be based on underlying diseases, type of jaundice, risk for vitamin K deficiency, and allergy to the drug.

Topics: Blood Coagulation Disorders; Drug-Related Side Effects and Adverse Reactions; Hemorrhagic Disorders; Humans; Injections; Malaria; Patient Selection; Vitamin K

Every year adverse drug events (ADEs) are known to be responsible for 98,000 deaths in the USA. Classical methods rely on report statements, expert knowledge, and staff operated record review. One of our objectives, in the PSIP project framework, is to use data mining (e.g., decision trees) to electronically identify situations leading to risk of ADEs. 10,500 hospitalization records from Denmark and France were used. 500 rules were automatically obtained, which are currently being validated by experts. A decision support system to prevent ADEs is then to be developed. The article examines a decision tree and the rules in the field of vitamin K antagonists.

Topics: Anticoagulants; Databases, Factual; Decision Trees; Drug-Related Side Effects and Adverse Reactions; Information Storage and Retrieval; Medical Informatics; Vitamin K

Timely reversal of excessive anticoagulation is important in preventing bleeding complications. The use of vitamin K in correcting over-anticoagulation is widely accepted to be superior to discontinuation of therapy but its effectiveness and safety in large scale cohort studies has not been assessed.. According to our protocol, 2 mg of oral vitamin K in addition to omitting the day's dose of warfarin, were administered to all patients presenting INR levels >or=5.0 and below 10.0; the INR values were checked 20 h after vitamin K administration. The rate of decay of INR, bleeding and thromboembolic complications at presentation and the following 30 days, as well as resistance to warfarin were assessed.. Of the 1,611 events, 1,043 (878 patients) met the selection criteria. The median (interquartile range) INR was 6.64 (6.12-7.52) at presentation (day zero) and fell to a median (interquartile range) INR of 2.72 (2.18-3.52, P < 0.0001) after the vitamin K administration (day one) and 90.6% of the INRs were below 4.5. In 98 (9.4%) instances the INR values did not fall below the safe limit of 4.5 and in 173 (17%) instances the INR values were overcorrected to below 2.0. Median INR value on day zero in these two groups was higher (7.3 vs. 6.6, P < 0.0001) and lower (6.5 vs. 6.7, P = 0.049) than that of the remaining cases, respectively. Overcorrection occurred more frequently in women (P = 0.0002). Female gender was an independent factor associated with INR overcorrection (P = 0.001; OR = 1.7, 95% CI 1.3-2.3). The INRs on day one were inside, above and below the therapeutic range in 44%, 36% and 20% respectively. Warfarin resistance was observed in six cases (0.6%). Major bleeding was reported in one case (1.1 per 100 patient-years), minor bleeding in 14 cases (16.1 per 100 patient-years) and thromboembolic events in six high risk patients (6.9 per 100 patient-years) during the one month period following vitamin K administration.. This adopted protocol for the reversal of excessive anticoagulation in asymptomatic or minor symptom presenting patients is easily applied, effective in lowering the INR and preventing complications. Its use in high risk thromboembolic patients warrants caution.

Topics: Aged; Aged, 80 and over; Anticoagulants; Antifibrinolytic Agents; Cohort Studies; Disease Management; Drug Evaluation; Drug Overdose; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Retrospective Studies; Sex Factors; Thromboembolism; Vitamin K; Warfarin

Topics: Animals; Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Fibrinolysis; Hemorrhage; Hemostasis; Heparin; Humans; Snake Venoms; Thrombocytopenia; Vitamin K; Warfarin

Topics: Anti-Inflammatory Agents; Anticoagulants; Aspirin; Drug-Related Side Effects and Adverse Reactions; Gastrointestinal Hemorrhage; Heparin; Humans; Vitamin K

Topics: Blood Coagulation Disorders; Drug-Related Side Effects and Adverse Reactions; Hemostasis; Humans; Iatrogenic Disease; Liver; Pharmacogenetics; Sex Factors; Vitamin K

Topics: Drug-Related Side Effects and Adverse Reactions; Isoniazid; Thioctic Acid; Vitamin A; Vitamin K; Vitamins

Topics: Coenzymes; Drug-Related Side Effects and Adverse Reactions; Emetine; Humans; Thiamine Pyrophosphate; Vitamin A; Vitamin K; Vitamins

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Vitamin A; Vitamin D; Vitamin K; Vitamins

Topics: Cysteine; Drug-Related Side Effects and Adverse Reactions; Glutathione; Radiation-Sensitizing Agents; Vitamin K

Topics: Drug-Related Side Effects and Adverse Reactions; Vitamin A; Vitamin D; Vitamin K; Vitamins

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Vitamin A; Vitamin D; Vitamin K; Vitamins

Topics: Ascorbic Acid; Drug-Related Side Effects and Adverse Reactions; Gold; Rheumatic Diseases; Vitamin A; Vitamin K; Vitamins