warfarin and Drug-Related-Side-Effects-and-Adverse-Reactions

The optimal antithrombotic therapy for atrial fibrillation (AF) patients undergoing coronary stenting is unknown. The present meta-analysis sought to investigate the efficacy and safety of triple therapy (TT; warfarin, clopidogrel and aspirin) vs dual antiplatelet therapy (DAPT; clopidogrel plus aspirin) in those patients.. PubMed and Cochrane Library were searched for studies enrolling AF patients undergoing coronary stenting on TT and DAPT up to September 2016, and fourteen studies were included. Efficacy outcomes included ischemic stroke, stent thrombosis, major adverse cardiovascular event (MACE), all-cause mortality and myocardial infarction (MI); safety outcome was major bleeding. We conducted meta-analysis and used odds ratio (OR) with 95% confidence intervals (CI) to compare TT and DAPT. Meta-regression, sensitivity and subgroup analysis were taken to investigate the source of heterogeneity in the outcome of major bleeding.. 14 eligible observational studies with 11,697 subjects were identified. Compared with DAPT, TT had decreased the risk of ischemic stroke [OR = 0.74, 95% CI (0.59, 0.93), P = 0.009] and stent thrombosis [OR = 0.40, 95% CI (0.18, 0.93), P = 0.033]. While, there was an increased risk of major bleeding [OR = 1.55, 95% CI (1.16, 2.09), P = 0.004] associated with TT. The risk of MACE, all-cause mortality and MI had no significant statistical difference between TT and DAPT. Furthermore, the results of univariate and multivariate meta-regression analysis implicated that there were no obvious correlations between certain baseline characteristics (age, gender, race, hypertension, study design) and risk of major bleeding. Also of major bleeding, the findings of sensitivity analysis were generally robust, and a prespecified subgroup analysis of race demonstrated that the source of heterogeneity might attribute to Asian studies mostly.. TT reduced the risk of ischemic stroke and stent thrombosis with an acceptable major bleeding risk compared with DAPT, and TT was considered as a valid alternative in AF patients undergoing coronary stenting. Further prospective randomized trials are needed to ensure the reliability of these data and find the optimal therapeutic strategy in this setting of patients.

Topics: Aspirin; Atrial Fibrillation; Clopidogrel; Drug Combinations; Drug-Related Side Effects and Adverse Reactions; Female; Fibrinolytic Agents; Hemorrhage; Humans; Hypertension; Male; Myocardial Infarction; Platelet Aggregation Inhibitors; Risk Factors; Stents; Stroke; Thrombosis; Warfarin

A comprehensive meta-analysis was performed to investigate whether the combination of high-/low-dose of aspirin and various intensities of warfarin (W) offer greater benefit than aspirin (ASA) alone. A total of 14 randomized clinical trials (RCTs) having 26,916 patients with acute coronary syndrome (ACS) met inclusion criteria. The efficacy and safety of all outcomes which included myocardial infarction (MI), all-cause death, stroke, and bleeding were calculated. The overall outcomes analysis showed there was no significant difference in the risk of MI (relative ratio [RR] 0.959, 95 % confidence interval [CI] 0.78-1.04, P = 0.308), stroke (RR 0.789, 95 % CI 0.57-1.09, P = 0.145), and all-cause death (RR 1.007, 95 % CI 0.93-1.09, P = 0.87) between the combination group and ASA group. The subgroup analysis suggested that ASA (≤100 mg/day) plus W (mean international normalized ratio [INR] 2.0-3.0) decreased the risk rate of stroke (RR 0.660, 95 % CI 0.50-0.87, P = 0.003). There was a lower risk of MI (RR 0.605, 95 % CI 0.47-0.77, P < 0.0001) as well as stroke (RR 0.594, 95 % CI 0.45-0.79, P < 0.0001) between W (INR 2.0-3.0) combined with ASA (mean dose ≥100 mg/day) and ASA. However, the risk of major bleeding (RR 1.738, 95 % CI 1.45-2.08, P < 0.0001) and minor bleeding (RR 2.767, 95 % CI 2.12-3.61, P < 0.0001) was almost doubled in the combined groups. Compared with ASA, high-dose aspirin with moderate-intensity warfarin (INR 2.0-3.0) may better reduce the risk of MI and stroke but confer an increased risk of bleeding.

Topics: Acute Coronary Syndrome; Adult; Aged; Anticoagulants; Aspirin; Causality; Comorbidity; Dose-Response Relationship, Drug; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Fibrinolytic Agents; Hemorrhage; Humans; Incidence; Male; Middle Aged; Risk Factors; Stroke; Survival Rate; Thromboembolism; Warfarin; Young Adult

1. Human-chimeric mice with humanized liver have been constructed by transplantation of human hepatocytes into several types of mice having genetic modifications that injure endogenous liver cells. Here, we focus on liver urokinase-type plasminogen activator-transgenic severe combined immunodeficiency (uPA/SCID) mice, which are the most widely used human-chimeric mice. Studies so far indicate that drug metabolism, drug transport, pharmacological effects and toxicological action in these mice are broadly similar to those in humans. 2. Expression of various drug-metabolizing enzymes is known to be different between humans and rodents. However, the expression pattern of cytochrome P450, aldehyde oxidase and phase II enzymes in the liver of human-chimeric mice resembles that in humans, not that in the host mice. 3. Metabolism of various drugs, including S-warfarin, zaleplon, ibuprofen, naproxen, coumarin, troglitazone and midazolam, in human-chimeric mice is mediated by human drug-metabolizing enzymes, not by host mouse enzymes, and thus resembles that in humans. 4. Pharmacological and toxicological effects of various drugs in human-chimeric mice are also similar to those in humans. 5. The current consensus is that chimeric mice with humanized liver are useful to predict drug metabolism catalyzed by cytochrome P450, aldehyde oxidase and phase II enzymes in humans in vivo and in vitro. Some remaining issues are discussed in this review.

Topics: Acetamides; Aldehyde Oxidase; Animals; Chimera; Cytochrome P-450 Enzyme System; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Hepatitis; Humans; Liver; Mice; Mice, SCID; Mice, Transgenic; Pharmaceutical Preparations; Pharmacokinetics; Pyrimidines; Rats; Urokinase-Type Plasminogen Activator; Warfarin

Topics: Anticoagulants; Biological Availability; Biotransformation; Blood Coagulation; Comparative Effectiveness Research; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Half-Life; Humans; Randomized Controlled Trials as Topic; Risk Adjustment; Stroke; Warfarin

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Tests; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Fondaparinux; Hemorrhage; Heparin; Humans; Polysaccharides; Practice Guidelines as Topic; Preoperative Care; Thrombosis; Warfarin

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

Our knowledge of the pharmacogenetics of warfarin and clopidogrel continues to expand as we learn more about the individual genetic variations that contribute to the drugs' efficacy and toxicity. We aim to review the recent developments in the field and discuss the clinical implications for the treatment of ischemic stroke patients. Despite recent advances, there is still insufficient data to suggest that routine genetic testing improves outcomes in patients treated with warfarin or clopidogrel for prevention of stroke.

Topics: Anticoagulants; Clopidogrel; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Genome-Wide Association Study; Humans; Pharmacogenetics; Platelet Aggregation Inhibitors; Stroke; Ticlopidine; Treatment Outcome; Warfarin

Warfarin remains the drug of choice for long-term anticoagulation management in a variety of conditions. Despite an established role in prevention of thromboembolic events such as stroke, warfarin continues to be underutilized because of its association with serious drug-related adverse events. Lacking alternative therapeutic approaches, intensive research in the past decade has focused on making anticoagulation with warfarin safer. Much emphasis has been placed on defining factors associated with the wide individual variability in warfarin dose. Polymorphic sites in three genes, cytochrome P450 (CYP) 2C9, vitamin K 2,3 epoxide reductase complex 1 (VKORC1), and CYP4F2, have been shown to affect stable warfarin dose. An overview of the persistent issues related to warfarin therapy and our current understanding of the genetic and clinical factors affecting warfarin dosing is presented. Finally, unresolved issues in improving clinical care of warfarin patients and future directions are provided.

Topics: Algorithms; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; Mixed Function Oxygenases; Pharmacogenetics; Stroke; Thromboembolism; Vitamin K Epoxide Reductases; Warfarin

In this review, we discuss the potential expectations, validity, predictive ability, and reality of pharmacogenetics in (1) titration of medication dose, (2) prediction of intended (efficacy) drug response, and (3) dose prediction of unintended (adverse) drug response. We expound on what these potential genetic predictors tell us and, more importantly, what they cannot tell us. Although pharmacogenetic markers have been hailed as promising tools, these proclamations are based mainly on associations rather than their evaluation as predictors. To put the expectations of the promise of pharmacogenetics in a realistic perspective, we review three examples. First, warfarin pharmacogenetics, wherein although the validity of the genetic variant dose is established and there is a validity of genetic variant-hemorrhage association, the clinical utility of testing is not clear. Second, the strong and clinically relevant HLA-Stevens-Johnson syndrome/toxic epidermal necrolysis association highlights the role of ethnicity. Third, the influence of CYP2D6 on tamoxifen efficacy, a model candidate with potential clinical utility but unclear validity. These examples highlight both the challenges and opportunities of pharmacogenomics. First, establishing a valid association between a genetic variation and drug response; second, doing so for a clinically meaningful outcome; and third, providing solid evidence or rationale for improvement in patient outcomes compared with current standard of care.

Topics: Anticoagulants; Antineoplastic Agents, Hormonal; Cytochrome P-450 CYP2D6; Dose-Response Relationship, Drug; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Genetic Variation; Genotype; Hemorrhage; Humans; Pharmacogenetics; Polymorphism, Genetic; Precision Medicine; Stevens-Johnson Syndrome; Tamoxifen; Warfarin

Chronic oral anticoagulation with warfarin is difficult to maintain within the therapeutic range and requires frequent monitoring and dose adjustments. Variations in two genes, VKORC1 and CYP2C9, have been associated with variation in warfarin metabolism among individuals. Patients with CYP2C9*2 and *3 variants have longer times to dose stabilization and are at higher risk of serious and life-threatening bleeding. VKORC1 polymorphisms significantly influence time to first therapeutic warfarin range, and variants in this gene determine low-, intermediate- and high-warfarin dose requirements. The prevalence of CYP2C9 and VKORC1 polymorphisms vary among different ethnic groups, and can account for over 30% of variance in warfarin dose. Recent studies suggest that the pharmacogenomics-guided dosing algorithm can accurately predict warfarin dosage and might reduce adverse events. We aim to review the pharmacogenetics of warfarin metabolism and the clinical role of genetic testing for warfarin therapy.

Topics: Algorithms; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cost-Benefit Analysis; Cytochrome P-450 CYP2C9; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Ethnicity; Humans; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Genetic; Vitamin K Epoxide Reductases; Warfarin

With the US Food and Drug Administration's recent label change of warfarin to include genetic testing for warfarin sensitivity, manufacturers are developing assays, and laboratories are offering testing. This article describes the genetic variants for which testing is available. Current technologies and assays are compared, including considerations for laboratories in choosing a method. Finally, laboratory issues that apply to all methods, such as quality control and proficiency testing as well as service issues including turn-around-time requirements are discussed.

Topics: Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; DNA Probes; Drug-Related Side Effects and Adverse Reactions; Genetic Testing; Humans; Mixed Function Oxygenases; Oligonucleotide Array Sequence Analysis; Pharmacogenetics; Polymerase Chain Reaction; Polymorphism, Genetic; Sequence Analysis, DNA; Vitamin K Epoxide Reductases; Warfarin

Pharmacogenetics (PGx) relies on the genetic makeup of an individual to predict drug response and efficacy, as well as potential adverse drug events. Significant advances in PGx research have been made since inherited differences in response to such drugs as isoniazid and succinylcholine were explored in the 1950s, and the clinical utility and application of PGx are especially apparent in some subspecialty areas of chemotherapeutic, psychotropic drug, and anticoagulant therapies.

Topics: Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Genetic Testing; Genotype; Government Regulation; Humans; Insurance, Health, Reimbursement; Mixed Function Oxygenases; Patient Selection; Pharmacogenetics; Phenotype; Physician's Role; Polymorphism, Genetic; Reagent Kits, Diagnostic; Reproducibility of Results; Risk Assessment; Vitamin K Epoxide Reductases; Warfarin

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

Pharmacogenomics is used to improve patient outcome by maximizing the likelihood of desired effects and minimizing the risk of adverse events using an individual's genetic profile. As such, pharmacogenomics can be used to improve current risk-management strategies (improving the risk-benefit balance). Two areas of great promise for pharmacogenomics in this regard are emerging: (i) the pharmacogenomics of modulating disease biomarkers (to provide insight into novel mechanisms of drug response and to identify the patients most likely to respond to a drug in a favorable way); and (ii) using pharmacogenomics to enhance drug safety. Given that novel biomarkers could enable the earlier detection of many diseases and more-widespread therapies for primary prevention, pharmacogenomics provides the opportunity to identify the patients most likely to respond to these therapies, thereby preserving valuable health-care resources. The use of pharmacogenomics in pharmacovigilance could also be useful for risk-stratifying patients and for helping to identify the mechanisms involved in adverse events.

Topics: 5-Lipoxygenase-Activating Proteins; Animals; Biomarkers; C-Reactive Protein; Carrier Proteins; Cyclooxygenase 2 Inhibitors; Drug-Related Side Effects and Adverse Reactions; Humans; Membrane Proteins; Pharmacogenetics; Safety; Warfarin

Topics: Adrenergic Agents; Aged; Aging; Anticoagulants; Brain; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Humans; Hypoglycemia; Pressoreceptors; Warfarin

Medications are commonly used in the elderly population. Because of a variety of treatments now available, many disease states now have very effective treatment. As a result, our elderly patients often take multiple medications. Due to various changes that occur, the elderly are at increased risk of adverse drug effects and drug toxicity potentially resulting in serious complications. Some medications have a greater potential to cause harm and these should be made aware to those who prescribe to elderly patients. Some of these medications should not be used if at all possible, while others, if used, need to be used with great caution, watching carefully for signs of problems. This article describes a variety of medications which have an increased potential for causing harm in elderly patients and gives alternatives of safer medications consideration.

Topics: Aged; Anti-Inflammatory Agents, Non-Steroidal; Antidepressive Agents, Tricyclic; Antipsychotic Agents; Barbiturates; Benzodiazepines; Digoxin; Drug-Related Side Effects and Adverse Reactions; Humans; Polypharmacy; Warfarin

Topics: Adverse Drug Reaction Reporting Systems; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Forecasting; Hemorrhage; Humans; 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

Adverse drug reactions are a significant cause of morbidity and mortality. Although many adverse drug reactions are considered nonpreventable, recent developments suggest these reactions may be avoided through individualization of drug therapies based on genetic information, an application known as pharmacogenomics.. To evaluate the potential role of pharmacogenomics in reducing the incidence of adverse drug reactions.. MEDLINE English-language only searches for adverse drug reaction studies published between January 1995 and June 2000 and review articles of variant alleles of drug-metabolizing enzymes published between January 1997 and August 2000. We also used online resources, texts, and expert opinion.. Detailed inclusion criteria were used to select studies. We included 18 of 333 adverse drug reaction studies and 22 of 61 variant allele review articles.. All the investigators reviewed and coded articles using standardized abstracting forms.. We identified 27 drugs frequently cited in adverse drug reaction studies. Among these drugs, 59% are metabolized by at least 1 enzyme with a variant allele known to cause poor metabolism. Conversely, only 7% to 22% of randomly selected drugs are known to be metabolized by enzymes with this genetic variability (range, P =.006-P<.001).. Our results suggest that drug therapy based on individuals' genetic makeups may result in a clinically important reduction in adverse outcomes. Our findings serve as a foundation for further research on how pharmacogenomics can reduce the incidence of adverse reactions and on the resulting clinical, societal, and economic implications.

Topics: Anticoagulants; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Pharmacogenetics; Polymorphism, Genetic; Warfarin

Topics: Adrenergic beta-Antagonists; Aged; Aged, 80 and over; Aging; Anticoagulants; Antihypertensive Agents; Benzothiadiazines; Diuretics; Drug Monitoring; Drug Prescriptions; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Sodium Chloride Symporter Inhibitors; Warfarin

Although drug-drug interactions constitute only a small proportion of adverse drug reactions, they are important because they are often predictable and therefore avoidable or manageable. Their frequency is related to the age of the patient, the number of drugs prescribed, the number of physicians involved in the patient's care and the presence of increasing frailty. The most important mechanisms for drug-drug interactions are the inhibition or induction of drug metabolism, and pharmacodynamic potentiation or antagonism. Interactions involving a loss of action of one of the drugs are at least as frequent as those involving an increased effect. It is likely that only about 10% of potential interactions result in clinically significant events and, while death or serious clinical consequences are rare, low-grade, clinically unspectacular morbidity in the elderly may be much more common. Nonspecific complaints (e.g. confusion, lethargy, weakness, dizziness, incontinence, depression, falling) should all prompt a closer look at the patient's drug list. There are a number of strategies that can be adopted to decrease the risk of potential clinical problems. The number of drugs prescribed for each individual should be limited to as few as is necessary. The use of drugs should be reviewed regularly and unnecessary agents withdrawn if possible, with subsequent monitoring. Patients should be encouraged to engage in a 'prescribing partnership' by alerting physicians, pharmacists and other healthcare professionals to symptoms that occur when new drugs are introduced. Physicians with a responsibility for elderly people in an institutional setting should develop a strategy for monitoring their drug treatment. For those interactions that have come to clinical attention, it is important to review why they happened and to plan for future prevention. Clinicians should also report, via the appropriate postmarketing surveillance scheme, any drug-drug interactions they have encountered. Finally, multidisciplinary education about the nature of physiological aging and its effect on drug handling, and the possible presentations of drug-related disease in older patients, is an important element in reducing interactions in the elderly.

Topics: Aged; Aging; Anticoagulants; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Health Services for the Aged; Humans; Warfarin

Topics: Alcohol Oxidoreductases; Catalase; Cholinesterases; Dicumarol; Diseases in Twins; Drug Hypersensitivity; Drug Resistance; Drug-Related Side Effects and Adverse Reactions; Environment; Female; Genetic Diseases, Inborn; Glaucoma; Glucosephosphate Dehydrogenase Deficiency; Hemoglobins; Humans; Infant, Newborn; Intraocular Pressure; Isoniazid; Malignant Hyperthermia; Mutation; Pharmaceutical Preparations; Pharmacogenetics; Phenylthiourea; Phenytoin; Pregnancy; Protein Binding; Racial Groups; Warfarin

Topics: Aged; Aged, 80 and over; Anticoagulants; Community Pharmacy Services; Croatia; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Patient Education as Topic; Pharmacists; Quality of Life; Rural Population; Surveys and Questionnaires; Warfarin

In the AMPLIFY clinical trial, apixaban was non-inferior to warfarin plus subcutaneous enoxaparin bridge therapy in the treatment of acute venous thromboembolism (VTE) and was associated with significantly less bleeding. This study evaluated their comparative effectiveness and safety in routine clinical practice. A matched-cohort design and data from four U.S. private health care claims databases were employed. Study population comprised patients who initiated outpatient treatment with apixaban versus warfarin (plus parenteral anticoagulant bridge therapy) within 30 days of their initial VTE episode; apixaban and warfarin patients were matched on age, characteristics of VTE episode, study database and propensity score. Major bleeding, clinically relevant non-major (CRNM) bleeding and recurrent VTE during the 180-day (maximum) follow-up period were compared using shared frailty models. During mean follow-up of 143 days among apixaban patients (

Topics: Adult; Aged; Anticoagulants; Case-Control Studies; Cohort Studies; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Male; Middle Aged; Practice Guidelines as Topic; Pyrazoles; Pyridones; Recurrence; Risk; United States; Venous Thromboembolism; Warfarin

Systemic thromboembolism and bleeding remain the two most common and serious complications of catheter ablation of atrial fibrillation. A variety of periprocedure anticoagulation strategies have been proposed to mitigate these risks. Although operators are now routinely administering dabigatran for anticoagulation in this setting, its relative safety and effectiveness compared to warfarin are unknown.. A total of 202 patients received dabigatran as part of their periprocedural anticoagulation regimen at the time of initial or redo catheter ablation for symptomatic atrial fibrillation. A comparison group of 202 patients treated with warfarin was randomly selected from patients undergoing atrial fibrillation (AF) ablation during the same time period. AF types were paroxysmal in 223 patients, persistent in 158 patients, and longstanding persistent in 13 patients. Mean age was 60.0 ± 10.5 years, 55 % had a history of hypertension, and mean CHADS-VASc score was 1.7 ± 1.3. "Continuous" warfarin or dabigatran was administered in 80 and 32 % of patients, respectively. Time to first dose of dabigatran post-procedure was 12.2 ± 10.3 h. Two dabigatran and no warfarin-treated patients had systemic thromboembolism (p = NS); five dabigatran and three warfarin-treated patients had bleeding complications (p = NS, combined endpoint p = 0.116). One dabigatran patient had severe pericardial bleeding (3 L blood loss).. In a retrospective pilot trial comparing the risks of systemic thromboembolism or bleeding complications in patients treated with warfarin or dabigatran anticoagulation, the outcomes were similar. A prospective trial is warranted.

Topics: Anticoagulants; Atrial Fibrillation; Benzimidazoles; beta-Alanine; Canada; Catheter Ablation; Comorbidity; Dabigatran; Decision Making; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Humans; Postoperative Complications; Premedication; Risk Factors; Thromboembolism; Treatment Outcome; United States; Warfarin

More than 1.6 million Americans currently reside in nursing homes. As many as 12% of them receive long-term anticoagulant therapy with warfarin. Prior research has demonstrated compelling evidence of safety problems with warfarin therapy in this setting, often associated with suboptimal communication between nursing home staff and prescribing physicians.. We conducted a randomized trial of a warfarin management protocol using facilitated telephone communication between nurses and physicians in 26 nursing homes in Connecticut in 2007-2008. Intervention facilities received a warfarin management communication protocol using the approach "Situation, Background, Assessment, and Recommendation" (SBAR). The protocol included an SBAR template to standardize telephone communication about residents on warfarin by requiring information about the situation triggering the call, the background, the nurse's assessment, and recommendations.. There were 435 residents who received warfarin therapy during the study period for 55,167 resident days in the intervention homes and 53,601 in control homes. In intervention homes, residents' international normalized ratio (INR) values were in the therapeutic range a statistically significant 4.50% more time than in control homes (95% confidence interval [CI], 0.31%-8.69%). There was no difference in obtaining a follow-up INR within 3 days after an INR value ≥4.5 (odds ratio 1.02; 95% CI, 0.44-2.4). Rates of preventable adverse warfarin-related events were lower in intervention homes, although this result was not statistically significant: the incident rate ratio for any preventable adverse warfarin-related event was .87 (95% CI, .54-1.4).. Facilitated telephone communication between nurses and physicians using the SBAR approach modestly improves the quality of warfarin management for nursing home residents.

Topics: Aged; Aged, 80 and over; Anticoagulants; Clinical Protocols; Communication; Connecticut; Drug-Related Side Effects and Adverse Reactions; Female; Homes for the Aged; Humans; International Normalized Ratio; Male; Middle Aged; Nursing Homes; Nursing Staff; Quality Assurance, Health Care; Telephone; Warfarin

To characterise the nature of the drug-related problems with warfarin therapy identified in pharmacist-conducted medication reviews during a collaborative post-discharge warfarin management service, with a focus on potentially serious drug interactions.. Australian community pharmacy practice.. Medication review reports submitted by pharmacists to patients' general practitioners as part of the service were reviewed and the type and clinical significance of the warfarin-associated drug-related problems, and the pharmacists' recommendations were classified. The prevalence of prescribing of 'potentially hazardous' warfarin drug interactions was investigated and compared with the frequency of documentation of these interactions in the medication review reports.. The number and nature of warfarin-associated drug-related problems identified and the rate of documentation of 'potentially hazardous' warfarin drug interactions in the reports from pharmacist-conducted medication reviews.. A total of 157 warfarin-associated drug-related problems were documented in 109 medication review reports (mean 1.4 per patient, 95% CI 1.3-1.6, range 0-5). Drug selection and Education or information were the most commonly identified warfarin-associated drug-related problems; most drug-related problems were of moderate clinical significance. Eight of 23 potentially serious warfarin drug interactions (34.8%) were identified in the medication review reports.. Pharmacists addressing drug selection and warfarin education drug-related problems during medication reviews may have contributed to the positive outcomes of the post-discharge service. Warfarin drug interactions were frequently identified; however, well-recognised potentially hazardous interactions were under-reported. Improved communication along the continuum of care would permit improved targeting of drug-related problem reporting, especially in relation to preventable drug interactions.

Topics: Cohort Studies; Community Pharmacy Services; Drug Interactions; Drug Utilization Review; Drug-Related Side Effects and Adverse Reactions; Humans; Patient Discharge; Pharmacists; Professional Role; Prospective Studies; Warfarin

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

This study was designed to evaluate safety and efficacy of combined low dose aspirin and warfarin therapy following mechanical heart valve replacement.. A total of 1496 patients (686 males, mean age 35±8.5 years) undergoing mechanical heart valvular replacement were randomly divided into study (warfarin plus 75-100 mg aspirin) or control (warfarin only) group. International normalized ratio (INR) and prothrombin time was maintained at 1.8-2.5 and 1.5-2.0 times of the normal value, respectively. Thromboembolic events and major bleedings were registered during follow up.. Patients were followed up for 24±9 months. The average dose of warfarin in the study and control group was 2.92±0.87 mg and 2.89±0.79 mg, respectively (p>0.05). The overall thromboembolic events in study group were lower than in control group (2.1% vs. 3.6%, p=0.044). No statistically significant differences were found in hemorrhage events (3.5% vs. 3.7%, p>0.05) or mortality (0.3% vs 0.4%, p>0.05) between the two groups.. Following mechanical valve replacement, combined low dose aspirin and warfarin therapy was associated with a greater reduction in thromboembolism events than warfarin therapy alone. This combined treatment was not associated with an increase in the rate of major bleeding or mortality.

Topics: Adult; Anticoagulants; Aspirin; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Heart Valve Prosthesis Implantation; Hemorrhage; Humans; International Normalized Ratio; Male; Prothrombin Time; Thromboembolism; Treatment Outcome; Warfarin; Young Adult

1 The awareness and recognition of adverse interactions between drugs by prescribers is low. 2 A 6-month prospective study on patients on long-term outpatient anticoagulant therapy in the Grampian area has been carried out to evaluate a simple and cheap warning system. 3 The practitioners of patients in the test group were issued with warning labels which showed drugs known to interact. A reduction in the initiation of prescriptions for potentially interacting drugs was shown between the test and control groups (no warning labels). 4 The 140 practitioners who completed the study found the system to be convenient and useful. Extension to other high-risk drugs with the potential to interact with other drugs is planned. This system has the advantage of being drug and patient-orientated whereas lists of drug interactions or drug discs require more conscious effort by the prescriber.

Topics: Barbiturates; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Surveys and Questionnaires; Warfarin

Topics: Accident Prevention; Aged; Anti-Bacterial Agents; Anticoagulants; Carbamazepine; Dibenzazepines; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Evaluation Studies as Topic; Female; Humans; Length of Stay; Male; Middle Aged; Migraine Disorders; Pharmaceutical Preparations; Phenobarbital; Placebos; Warfarin

In Denmark, physicians are legally obliged to report serious adverse drug reactions (ADRs), such as intracranial hemorrhage (ICH) following anticoagulant (AC) treatment, to the Danish Medicines Agency. We were therefore puzzled to discover a high number of reports concerning ICHs following treatment with the direct oral anticoagulants (DOACs) dabigatran, rivaroxaban, and apixaban compared with warfarin. This was surprising, as all DOACs have been found to be associated with a lower risk of ICH compared with warfarin in phase III randomized controlled trials.. The primary aim of the study was to estimate the level of underreporting of ICH as an ADR following treatment with warfarin, dabigatran, rivaroxaban, and apixaban.. This observational study covered a 5-year period (2014-2018). Using nationwide registries held by the Danish Health Data Authority, the number of users, exposure time in person-years, and related ICH events for each of the study drugs were estimated. Data on ADR-ICH reports were extracted from the interactive ADR overviews held by the Danish Medicines Agency.. From 2014 to 2018, 97.0% of the identified warfarin-related ICH events were not reported as ADRs. For the DOACs, the level of underreporting ranged from 88.8 to 90.8%.. We found a heavy and differentiated level of underreporting of ICH as an ADR following treatment with the four study drugs.

Topics: Anticoagulants; Atrial Fibrillation; Dabigatran; Denmark; Drug-Related Side Effects and Adverse Reactions; Humans; Intracranial Hemorrhages; Pyridones; Rivaroxaban; Warfarin

With the availability of detailed genomic data on all 57 human cytochrome P450 genes, it is clear that there is substantial variability in gene product activity with functionally significant polymorphisms reported across almost all isoforms. This article is concerned mainly with 13 P450 isoforms of particular relevance to xenobiotic metabolism. After brief review of the extent of polymorphism in each, the relevance of selected P450 isoforms to both adverse drug reaction and disease susceptibility is considered in detail. Bleeding due to warfarin and other coumarin anticoagulants is considered as an example of a type A reaction with idiosyncratic adverse drug reactions affecting the liver and skin as type B. It is clear that CYP2C9 variants contribute significantly to warfarin dose requirement and also risk of bleeding, with a minor contribution from CYP4F2. In the case of idiosyncratic adverse drug reactions, CYP2B6 variants appear relevant to both liver and skin reactions to several drugs with CYP2C9 variants also relevant to phenytoin-related skin rash. The relevance of P450 genotype to disease susceptibility is also considered but detailed genetic studies now suggest that CYP2A6 is the only P450 relevant to risk of lung cancer with alleles associated with low or absent activity clearly protective against disease. Other cytochrome P450 genotypes are generally not predictors for risk of cancer or other complex disease development.

Topics: Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Disease Susceptibility; Drug-Related Side Effects and Adverse Reactions; Genotype; Humans; Pharmacogenetics; Warfarin

Drug-related problems (DRPs) in a pharmacist-managed anticoagulation clinic (AC) have not been extensively studied. We aimed to characterize the DRPs in a pharmacist-managed AC, identify the factors associated with the solved status of DRPs, and analyze the secondary outcomes, including the safety and efficacy of AC service. The patients receiving services at a pharmacist-managed AC in a medical center for the first time from March 2019 to August 2020 were reviewed retrospectively. The DRPs were retrieved from a self-developed Intelligent AC Service System and classified according to the Pharmaceutical Care Network Europe Foundation v9.0 classification system. Logistic regression models were performed to identify the potential factors associated with the solved status of DRPs. A total of 78 direct oral anticoagulant (DOAC) and 34 warfarin users were included. The major types of DRPs identified at the initial service were adverse drug events (ADEs) (68.4%) and untreated symptoms or indications (14.8%) in the DOAC group, and ADEs (51.6%) and suboptimal effect of drug treatment (38.7%) in the warfarin group. The rates of totally solved DRPs were 56.8% and 51.6% in the DOAC and warfarin groups, respectively. According to the multivariable analysis, receiving AC services 3 times or more in 180 days (OR 3.11, 95% CI 1.30-7.44) was associated with the totally solved status of DRPs in the DOAC group, but no relevant factor was identified in the warfarin group. The secondary outcomes showed that DOAC users demonstrated fewer thromboembolism events, major bleeding, and bleeding-related hospitalizations after AC services, whereas the warfarin users increased percentage time in therapeutic range (TTR% 55.0% vs. 74.6%, P = 0.006) after AC services. These findings may be utilized to develop DOAC and warfarin AC services.

Topics: Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Factor Analysis, Statistical; Humans; Pharmacists; Retrospective Studies; Warfarin

Pharmacovigilance (PV) has proven to detect post-marketing adverse drug events (ADE). Previous research used the natural language processing (NLP) tool to extract unstructured texts relevant to ADEs. However, texts without context reduce the efficiency of such algorithms. Our objective was to develop and validate an innovative NLP tool, aTarantula, using a context-aware machine-learning algorithm to detect existing ADEs from social media using an aggregated lexicon.. aTarantula utilized FastText embeddings and an aggregated lexicon to extract contextual data from three patient forums (i.e., MedHelp, MedsChat, and PatientInfo) taking warfarin. The lexicon used warfarin package inserts and synonyms of warfarin ADEs from UMLS and FAERS databases. Data was stored on SQLite and then refined and manually checked by three clinical pharmacists for validation.. Multiple organ systems where the most frequent ADE were reported at 1.50%, followed by CNS side effects at 1.19%. Lymphatic system ADEs were the least common side effect reported at 0.09%. The overall Spearman rank correlation coefficient between patient-reported data from the forums and FAERS was 0.19. As determined by pharmacist validation, aTarantula had a sensitivity of 84.2% and a specificity of 98%. Three clinical pharmacists manually validated our results. Finally, we created an aggregated lexicon for mining ADEs from social media.. We successfully developed aTarantula, a machine-learning algorithmn based on artificial intelligence to extract warfarin-related ADEs from online social discussion forums automatically. Our study shows that it is feasible to use aTarantula to detect ADEs. Future researchers can validate aTarantula on the diverse dataset.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Drug-Related Side Effects and Adverse Reactions; Humans; Machine Learning; Pharmacovigilance; Social Media; Warfarin

Background Oral anticoagulants are established drugs of choice for the prevention and treatment of thromboembolic events. However, monitoring their safety remains warranted. Objective The aim was to analyze spontaneous reports of adverse drug reactions related to oral anticoagulants in the Czech Republic. Setting Retrospective observational pharmacovigilance study. Methods Adverse drug reaction reports were obtained from the State Institute for Drug Control between January 2005 and November 2017. Reports related to warfarin, dabigatran, apixaban, and rivaroxaban received from healthcare professionals and patients were analyzed. Main outcome measure Frequency and nature of adverse drug reactions reported to oral anticoagulants. Results In total, 297 reports containing 672 adverse drug reactions were received; 269 reports were sent by healthcare professionals (85% by physicians). In 65% of all reports, reactions were due to direct oral anticoagulants. A higher total number of adverse drug reactions was associated with direct oral anticoagulants than with warfarin [reporting odds ratio (ROR): 10.76; confidence interval (CI): 8.70-13.32; p < 0.001]. Along with the increasing utilization of direct oral anticoagulants, the reporting rate gradually declined over time, especially for rivaroxaban and apixaban. Fatal outcomes were reported in 7%, mostly for dabigatran. Hemorrhagic reactions were the most frequently reported adverse drug reactions (37% associated with dabigatran, 28% with apixaban, 24% with warfarin, and 23% with rivaroxaban), and compared to warfarin, they were significantly more often associated with direct oral anticoagulants (ROR: 14.36; CI: 9.57-21.54; p < 0.001). Conclusion The number of adverse drug reaction reports related to oral anticoagulants in the Czech Republic was relatively low, compared to other studies, but 96% of the cases were serious. Data from spontaneous adverse drug reactions reporting should be further analyzed in order to obtain additional information on the safety profile of oral anticoagulants.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Czech Republic; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Humans; Retrospective Studies; Stroke; Warfarin

Limited information is available on anticoagulant-related nephropathy (ARN). We therefore reviewed the Japanese Adverse Drug Event Report database to investigate kidney injury (KI) in patients administered warfarin or direct oral anticoagulants (DOACs) and sought to clarify the risk factors for ARN. KI risk in warfarin users was associated with male sex (odds ratio [OR], 1.70; 95% confidence interval [CI], 1.35-2.13; P < .01) and age ≥80 years (OR, 1.35; 95% CI, 1.07-1.72; P = .01). KI risk in DOAC users was associated with body weight ≥80 kg (OR, 1.60; 95% CI, 1.01-2.53; P = .04) and use of dabigatran (OR, 1.61; 95% CI, 1.09-2.37; P < .01). Our findings suggest that risk factors for ARN differ between warfarin and DOACs and that these risk factors may be associated with bleeding risk. Therefore, the risk of ARN may be decreased by better managing bleeding risk in patients taking anticoagulants.

Topics: Administration, Oral; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Humans; Japan; Male; Risk Factors; Rivaroxaban; Stroke; Warfarin

Medication-related harm represents a significant issue for patient safety and quality of care. One strategy to avoid preventable adverse drug events is to utilize patient-specific factors such as pharmacogenomics (PGx) to individualize therapy.. We measured the number of patients enrolled in a health-system biobank with actionable PGx results who received relevant medications and assessed the incidence of adverse drug events (ADEs) that might have been prevented had the PGx results been used to inform prescribing.. Patients with actionable PGx results in the following four genes with Clinical Pharmacogenetics Implementation Consortium (CPIC) guidelines were identified: HLA-A*31:01, HLA-B*15:02, TPMT, and VKORC1. The patients who received interacting medications (carbamazepine, oxcarbazepine, thiopurines, or warfarin) were identified, and electronic health records were reviewed to determine the incidence of potentially preventable ADEs.. Of 36,424 patients with PGx results, 2327 (6.4%) were HLA-A*31:01 positive; 3543 (9.7%) were HLA-B*15:02 positive; 2893 (7.9%) were TPMT intermediate metabolizers; and 4249 (11.7%) were homozygous for the VKORC1 c.1639 G>A variant. Among patients positive for one of the HLA variants who received carbamazepine or oxcarbazepine (n = 92), four (4.3%) experienced a rash that warranted drug discontinuation. Among the TPMT intermediate metabolizers who received a thiopurine (n = 56), 11 (19.6%) experienced severe myelosuppression that warranted drug discontinuation. Among patients homozygous for the VKORC1 c.1639 G>A variant who received warfarin (n = 379), 85 (22.4%) experienced active bleeding and/or international normalized ratio (INR) > 5 that warranted drug discontinuation or dose reduction.. Patients with actionable PGx results from a health-system biobank who received relevant medications experienced predictable ADEs. These ADEs may have been prevented if the patients' PGx results were available in the electronic health record with clinical decision support prior to prescribing.

Topics: Biological Specimen Banks; Drug-Related Side Effects and Adverse Reactions; HLA-A Antigens; HLA-B Antigens; Humans; Oxcarbazepine; Pharmacogenetics; Vitamin K Epoxide Reductases; Warfarin

Direct-acting oral anticoagulants (DOACs) are replacing conventional VKA (vitamin K antagonist, i.e., warfarin) for various indications where a therapeutic anticoagulant effect is desired. We evaluated the prescribing patterns of the DOACs and warfarin, cost implications of the increasing DOACs prescribing, and deduce the reporting of serious and fatal events, during 2009-2019 in primary care England. Prescriptions and fatal or serious adverse events reporting data, between 2009 and 2019 were analysed, using linear regression to examine the trends in prescriptions, costs, and serious and fatal events reporting. We also compared the prescribing trends of four direct-acting oral anticoagulants and warfarin, normalised to per 1000 clinical commissioning group (CCG) patient population for the year 2019 to better understand the regional differences in DOACs prescribing. The overall use of any DOACs (as a proportion of total anticoagulants) increased from 16% in 2015 to 62% in 2019 with an average increase of 87% (95% CI 83.1, 90.5) per year. The reporting of serious and fatal events associated with DOACs decreased by 6% (95% CI 12.5, - 0.1) per year. Apixaban is by far the most prescribed with an average drug cost increasing to 156% (95% CI 140, 172) per year. In England, the lowest anticoagulant prescribing region was Greater London whereas the highest prescribing regions were Yorkshire and Humber for DOACs and the East Midlands for warfarin. Interestingly, Lancashire, Merseyside, and Cheshire showed a higher usage for warfarin over DOACs. The differing prescription patterns could be a result of changes in national guidelines and increasing population. Nevertheless, DOACs appear to make an increasing contribution to total anticoagulant prescription items and costs.

Topics: Administration, Oral; Anticoagulants; Atrial Fibrillation; Drug-Related Side Effects and Adverse Reactions; England; Factor Xa Inhibitors; Humans; Practice Patterns, Physicians'; Stroke; Warfarin

Patients who require urgent warfarin reversal often receive four-factor prothrombin complex concentrate (4F-PCC), which is traditionally dosed according to weight and initial INR. Our institution implemented a fixed-dose 4F-PCC strategy, using an initial dose of 1500 units. We evaluated the frequency with which the initial fixed dose 4F-PCC was inadequate, as defined by need for supplemental dosing. As part of the protocol, if the initial fixed-dose 4F-PCC is administered and does not achieve INR goal, then the remainder of the standard weight- and INR-based dosing can be given. During the study period, 63 patients on warfarin received 4F-PCC using the fixed-dose protocol. Based on the INR following 4F-PCC administration, 11 patients (17%) were eligible to receive a supplemental dose based on failure to achieve their specified INR goal. Two of the 11 patients eligible for supplemental 4F-PCC dosing received the second dose, both with initial supratherapeutic INRs > 3.5. We found that most patients given an initial fixed-dose 4F-PCC achieved their INR goals, and of those who did not, most did not receive supplemental dosing, suggesting that clinical providers felt that adequate hemostasis had been achieved. In addition, fixed-dose 4F-PCC was able to be given rapidly, with few dosing errors, suggesting that this is a reasonable option for 4F-PCC delivery.

Topics: Aged, 80 and over; Blood Coagulation Factors; Body Weight; Clinical Protocols; Dose-Response Relationship, Drug; Drug Dosage Calculations; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Female; Humans; International Normalized Ratio; Male; Outcome and Process Assessment, Health Care; Retrospective Studies; Warfarin

Trials and past observational work compared dabigatran and warfarin in patients with atrial fibrillation, but few reported estimates of absolute harm and benefit under real-world adherence patterns, particularly in older adults that may have differing benefit-harm profiles. We aimed to estimate risk differences for ischemic stroke, death, and gastrointestinal bleeding after initiating dabigatran and warfarin in older adults (a) when patients adhere to treatment and (b) under real-world adherence patterns.. In a 20% sample of nationwide Medicare claims from 2010 to 2015, we identified beneficiaries aged 66 years and older initiating warfarin and dabigatran. We followed individuals from initiation until death or October 2015 (initial treatment, IT) and separately censored individuals' follow-up after drug switches and gaps in supply (on-treatment, OT). We applied inverse probability of treatment and standardized morbidity ratio weights, as well as inverse probability of censoring weights, to estimate two-year risk differences (RDs) for dabigatran vs warfarin.. We identified 10,717 dabigatran and 74,891 warfarin initiators. Weighted OT RDs suggested decreased ischemic stroke risk for dabigatran vs warfarin; IT RDs indicated increased or no change in ischemic stroke risk. Regardless of follow-up approach and weighting strategy, risk of death appeared lower and risk of gastrointestinal bleeding appeared higher when comparing dabigatran vs warfarin.. Dabigatran use was associated with lower risks of mortality and ischemic stroke in routine care when older adults stayed on treatment. IT analyses suggested that these benefits may be diminished under real-world patterns of switching and discontinuation.

Topics: Age Factors; Aged; Aged, 80 and over; Antithrombins; Atrial Fibrillation; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Hemorrhage; Health Services for the Aged; Humans; Male; Medicare; Risk Factors; Stroke; United States; Warfarin

While warfarin is the most commonly prescribed medication to prevent thromboembolic disorders, the risk of adverse drug reactions (ADR) poses a serious concern. This prospective study evaluated how primary care providers (PCP) and cardiologists at our Institution managed patients treated with warfarin with the goal of decreasing the number of warfarin ADRs.. A multidisciplinary anticoagulation task force was established at our Institution in 2014 to standardize warfarin monitoring and management. Between 2013 and 2017, we analyzed patients who were prescribed warfarin by their PCP or cardiologist upon hospital discharge and in the ambulatory setting to determine the international normalized ratio (INR) within 5, 10, and 30 days after discharge, time in therapeutic range (TTR), number of severe warfarin ADRs, and total and average cost reduction of all severe warfarin ADRs to determine whether there was an organizational cost savings following the implementation of standardized warfarin care.. The warfarin ADR rate significantly decreased over the 5-year period, from 3.8 to 0.98% (p < 0.0001). The proportion of warfarin prescriptions out of all anticoagulants significantly decreased, from 72.2 to 42.1% (p < 0.001). The proportion of individuals who received an INR at 5, 10, and 30 days after hospital discharge compared to the total number of patients prescribed warfarin significantly increased (p < 0.001). The total cost of severe warfarin ADRs decreased by 57.6% between 2013 and 2017.. This study serves as a model to reduce the number of severe warfarin ADRs by the following tactics: (1) educating PCPs and cardiologists about evidence-based guidelines for warfarin management, (2) increasing the use of our Institution's electronic warfarin module, and (3) enhancing patient compliance with obtaining INR.

Topics: Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Humans; International Normalized Ratio; Patient Compliance; Physicians, Family; Prospective Studies; Warfarin

This study aimed to compare and determine the prevalence of drug-drug interaction (DDI) and bleeding rate in atrial fibrillation (AF) patients receiving anticoagulants in a clinical setting. We used large claims data of AF patients obtained from the Japan Medical Data Center. The prevalence of DDIs and cases leading to bleeding events were surveyed clinically relevant DDIs extracted from 1) reported from a spontaneous adverse event reporting system (Japanese Adverse Drug Events Report system; JADER) ≥4 patients; 2) DDIs cited in the package inserts of each anticoagulant (each combination assessed according to "Drug interaction 2015" list; 3) warfarin and quinolone antibiotics DDIs. DDIs were categorized the mechanisms for pharmacokinetic DDI (Cytochrome P450 (CYP) or transporter etc. that modulate blood concentration of anticoagulants)/pharmacodynamic DDI (combination with similar pharmacological actions) or both in the analysis for each patients' prescriptions obtained from a claims data. AF patients were compared between cases with and without bleeding after administered of anticoagulants. Bleeding was observed in 220/3290 (6.7%) AF patients. The bleeding rate in patients with both pharmacokinetic and pharmacodynamic DDI mechanisms (26.3%) was higher than that in patients with either mechanism (8.6% and 9.2%, respectively) or without DDIs (4.9%). The odds ratio for bleeding in AF patients with both of pharmacokinetic and pharmacodynamic was (7.18 [4.69-11.00], p<0.001). Our study concluded multi mechanism based DDIs leads serious outcome as compared to that of single mechanism based DDIs in AF patients. We determined the prevalence and frequency of bleeding for anticoagulant-related DDIs. To manage DDIs, both pharmacokinetic and pharmacodynamic DDI mechanisms should be closely monitored for initial symptoms of bleeding within the first 3 months.

Topics: Adolescent; Adult; Aged; Anticoagulants; Atrial Fibrillation; Child; Child, Preschool; Databases, Factual; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Infant; Male; Middle Aged; Prevalence; Warfarin; Young Adult

Epistaxis is one of the more common reasons for emergency room visits. The main risk factor for epistaxis is anticoagulant therapy. Until recently, the main culprit was oral intake of a vitamin K antagonist, such as warfarin, which has a number of side effects. Even more recently, several direct oral anticoagulants, rivaroxaban and dabigatran, have been approved for use. We investigated the possible differences between treatment of epistaxis with direct oral anticoagulants and vitamin K antagonists.. We conducted a retrospective cohort study at a tertiary referral center in Germany. All patients who were admitted within a 1-year period were included. Patient files were used to obtain the information.. Overall, 677 patients were included in our study. Of these, 159 had been treated with vitamin K antagonists and 49 with direct oral anticoagulants. There were no significant differences in terms of age (p = 0.592), sex (p = 0.372), vital signs, bloodwork, or location of bleeding (p = 0.372). Management of epistaxis between the groups was also comparable (p = 0.399), with similar hospital admission rates (37.1% vs 24.5%; p = 0.145) and duration of stay (3.5 ± 2.1 days vs 3.8 ± 3.3 days; p = 0.650).. We found no evidence to suggest epistaxis is more severe or requires more invasive therapy in patients given direct oral anticoagulants. A significant proportion of patients on vitamin K antagonists were not within the target range for international normalized ratio, highlighting one of the main issues with oral anticoagulation by vitamin K antagonists.

Topics: Administration, Oral; Aged; Aged, 80 and over; Anticoagulants; Cohort Studies; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Epistaxis; Female; Follow-Up Studies; Germany; Hospitalization; Humans; Length of Stay; Male; Retrospective Studies; Risk; Rivaroxaban; Treatment Outcome; Warfarin

In-hospital adverse medication events result in increased morbidity and mortality. Many implicated drugs carry pharmacogenomic information. We hypothesized that comprehensive pre-emptive pharmacogenomic profiling could have high relevance for in-hospital prescribing.. We retrospectively analyzed the in-hospital medications of a genotyped outpatient cohort admitted at our institution from 2012 to 2015. The endpoints were medication changes (new medications initiated, dose adjustments, or medications discontinued) involving drugs with pharmacogenomic annotations from three sources: Clinical Pharmacogenetics Implementation Consortium guidance, Food and Drug Administration label information, and drugs with clinical decision supports in our institutional pharmacogenomic Genomic Prescribing System.. Of 867 genotyped outpatients, 20 were hospitalized (mean: 78.2 years, 65% male). This hospitalized cohort was significantly older (78.2 vs. 61.3 years, P<0.0001) and took more medications (8.9 vs. 5.0 medications, P<0.0001). Out of 159 medication changes made, most (67.9%) were new medications (average: 2.5/hospitalization) with one-third of these having clinically annotated pharmacogenomic information. Half of all hospitalizations involved at least one pharmacogenomic medication. Over half (55%) of the hospitalized cohort was newly prescribed at least one of eight key pharmacogenomic medications, including high-risk drugs such as clopidogrel, codeine, and warfarin.. Our study suggested that older patients and those with polypharmacy were at increased risk for hospitalizations, where many new prescriptions included frequently used pharmacogenomic drugs. Targeting this group for pre-emptive genotyping would facilitate the delivery of highly relevant information to inform inpatient prescribing.

Topics: Aged; Aged, 80 and over; Clopidogrel; Codeine; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Hospital Mortality; Hospitalization; Humans; Male; Middle Aged; Pharmacogenetics; Pharmacogenomic Variants; Prescription Drugs; Warfarin

Patients with nonvalvular atrial fibrillation (NVAF) often have multiple comorbidities requiring concomitant medications in addition to their oral anticoagulant (OAC). The objective of this study was to evaluate the impact of polypharmacy on the effectiveness and safety of rivaroxaban versus warfarin in patients with NVAF managed in routine clinical practice.. Retrospective claims analysis.. United States Truven MarketScan database (November 2012-March 2017).. Adults who were OAC naïve during the 12 months before the day of the first qualifying rivaroxaban or warfarin dispensing (index date); had at least two International Classification of Diseases, Ninth or Tenth Revision diagnosis codes for atrial fibrillation without codes suggesting valvular heart disease; had at least 12 months of continuous insurance coverage prior to the qualifying OAC dispensing; and were experiencing polypharmacy (concomitant prescription claims for five or more unique chronic medication claims) were included. Patients who had concomitant prescription claims for ≥ 10 unique chronic medication claims constituted the substantial polypharmacy cohort used in the secondary analysis. Patients receiving rivaroxaban were propensity-score matched in a 1:1 ratio to patients receiving warfarin (13,981 patients in each polypharmacy OAC group, and 1765 patients in each substantial polypharmacy OAC group).. Patients were followed until occurrence of an event (stroke or systemic embolism [SSE] combined [primary effectiveness outcome] or major bleeding [primary safety outcome]), OAC discontinuation or switch (30-day permissible gap), insurance disenrollment, or end of follow-up period. Rates of SSE, ischemic stroke, and major bleeding were compared by using Cox regression, reported as hazard ratios (HRs) and 95% confidence intervals (CIs). In patients with NVAF taking five or more chronic medications, rivaroxaban was associated with a 34% (95% CI 12-50) and 40% (95% CI 16-57) hazard reduction of SSE and ischemic stroke, respectively. Occurrence of major bleeding was similar between OAC cohorts (HR 1.08, 95% CI 0.92-1.28). A secondary analysis in patients with NVAF with substantial polypharmacy (taking ≥ 10 chronic medications) was also performed. Similar trends in SSE (HR 0.44), ischemic stroke alone (HR 0.62), and major bleeding (HR 1.07) were observed in patients with NVAF who had substantial polypharmacy, although 95% CIs crossed 1.0 for each outcome in this smaller study cohort.. This real-world study suggests that in the setting of polypharmacy and NVAF, rivaroxaban is an effective and safe alternative to warfarin.

Topics: Aged; Anticoagulants; Atrial Fibrillation; Comorbidity; Databases, Factual; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Health Services for the Aged; Humans; Insurance Claim Review; Male; Polypharmacy; Retrospective Studies; Rivaroxaban; United States; Warfarin

Background Medicine use review by pharmacists has the potential to improve anticoagulation therapy management in patients on warfarin. Objective To develop, implement and evaluate a pharmacist-led medication use review service for patients on warfarin. Setting Six community pharmacies in Malta. Method Patients (N = 100) aged 18 or older and on warfarin were recruited through pre-selected community-pharmacies. These patients were then invited to attend two sessions: a review session (t

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Community Pharmacy Services; Drug Utilization Review; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Humans; International Normalized Ratio; Male; Malta; Medication Reconciliation; Middle Aged; Pharmacists; Professional Role; Retrospective Studies; Warfarin

Polypharmacy and age are known to increase the risk for potential drug interactions. Type 2 diabetes has been associated with polypharmacy and several comorbidities. Currently, there is no information on whether the frequency of clinically relevant drug-drug interactions and the risk for drug adverse effects differ between older persons with and without diabetes. The aim of this study was to investigate the frequency of drug-drug interactions and the risk for drug adverse effects in these two groups in primary care.. The basic study population consisted of Finnish home-dwelling primary care patients aged ≥ 65 years (N = 3039). For each person with diabetes, two controls were selected with adjusted age and gender. To collect data, electronic primary care patient records, a structured health questionnaire and a structured health examination conducted by a physician were utilized. Using the SFINX-PHARAO. There were no significant differences in the frequency of drug-drug interactions or the risk for drug adverse effects in persons with and without diabetes. At least one clinically relevant interaction was found in 81 (44.5%) persons with diabetes and 73 (41.5%) persons without diabetes. The most common drugs causing interactions included non-steroidal anti-inflammatory drugs (NSAIDs) and warfarin.. There is no difference in the frequency of drug-drug interactions or risk for drug adverse effects in older home-dwelling persons with and without diabetes. Due to common comorbidities and commonly used drugs among persons with diabetes, drug-drug interactions involving warfarin or NSAIDs in particular should be carefully monitored to avoid drug adverse effects.

Topics: Aged; Comorbidity; Diabetes Mellitus, Type 2; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Finland; Humans; Male; Polypharmacy; Practice Patterns, Physicians'; Primary Health Care; Surveys and Questionnaires; Warfarin

Topics: Adolescent; Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Female; Hospitals, University; Humans; Male; Registries; Sweden; Warfarin

Developing an optimal medication strategy poses a challenging task in fragile patients after left atrial appendage closure (LAAC). We report an optimal nonvitamin K antagonist oral anticoagulant (NOAC) therapy in a warfarin-sensitive patient after LAAC.. A 77-year-old nonvalvular atrial fibrillation (NVAF) male carrying 2 warfarin-sensitive alleles experienced 2 gum-bleeding with the international normalized ratio (INR) around 3.. Persistent NVAF with a history of subtotal gastrectomy and moderate renal insufficiency.. Warfarin was discontinued and vitamin K1 was immediately administrated via intravenous infusion. LAAC was regarded as a preferable option, and rivaroxaban 15 mg daily was managed after LACC.. Complete endothelialization on the surface of device was detected via transoesophageal echocardiography (TEE), and no peridevice spillage and adverse event occurred.. A post-LAAC treatment with NOAC may be a viable regimen in patients intolerant to warfarin.

Topics: Aged; Anticoagulants; Atrial Appendage; Atrial Fibrillation; Cardiac Surgical Procedures; Drug-Related Side Effects and Adverse Reactions; Echocardiography, Transesophageal; Humans; Male; Pharmacogenomic Testing; Postoperative Care; Prosthesis Implantation; Risk Adjustment; Rivaroxaban; Septal Occluder Device; Treatment Outcome; Warfarin

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

Oral candidiasis is a frequently encountered oral fungal infection which can be treated with systemic and topical antifungal agents. Warfarin is a widely used oral anticoagulant. The interaction of miconazole oral gel and warfarin, causing potentiation of anticoagulant activity, has been documented over many years with evidence of occurrence in multiple settings and is a significant patient safety risk. This dangerous interaction remains underappreciated by dentists, doctors, pharmacists and patients, with resulting significant morbidity and mortality still occurring. This paper reports on recent developments concerning this interaction, and the important patient safety issues involved. In situations where topical treatment for oral candidiasis is indicated, nystatin should be prescribed instead of miconazole oral gel in patients taking warfarin, unless close monitoring and titration of the anticoagulant effect is undertaken.

Topics: Administration, Topical; Aged; Aged, 80 and over; Anticoagulants; Antifungal Agents; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Gels; Humans; Male; Miconazole; Middle Aged; Warfarin

The aim of this study was to obtain a better insight into the adverse effects profiles of the new direct-acting oral anticoagulants (DOACs).. A review was undertaken of all reports of adverse effects for warfarin, dabigatran, rivaroxaban and apixaban reported to the regional medicines information and pharmacovigilance centres (RELIS) in the period June 2013-May 2015.. Approximately 65 000 persons used direct-acting oral anticoagulants and 80 000 used warfarin in the period of the study. A total of 409 reports of adverse effects were included. Altogether 55 % of the reports applied to men. In 76 % of the reports for direct-acting oral anticoagulants and 85 % for warfarin, the patients were more than 70 years of age. The most common adverse effects were haemorrhages (48 % for direct-acting oral anticoagulants and 75 % for warfarin), most of which were cerebral haemorrhages (91 for direct-acting oral anticoagulants and 92 for warfarin). Blood clots (therapeutic failure), cognitive effects, headache and hair loss were some of the other adverse effects. The highest comorbidity was among the patients who died. The number of reported deaths was highest for rivaroxaban (1.1 deaths/1000 users) with a declining incidence for apixaban (0.9 ‰), dabigatran (0.7 ‰) and warfarin (0.6 ‰). There were different degrees of reporting for these medications, and the spontaneous reporting system cannot therefore be used to compare the incidence of adverse effects for the drugs.. Adverse effects, including serious effects, may occur when using all anticoagulants. Factors that may increase the risk of adverse effects are advanced age, high comorbidity, reduced renal function, and polypharmacy.

Topics: Age Distribution; Anticoagulants; Cerebral Hemorrhage; Comorbidity; Dabigatran; Databases, Factual; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Male; Pyrazoles; Pyridones; Registries; Risk Factors; Rivaroxaban; Sex Distribution; Time Factors; Warfarin

Patients with severely reduced renal function have been excluded from randomized controlled trials of oral anticoagulation in atrial fibrillation (AF). Warfarin treatment in this population is controversial and data on anticoagulation control and the impact on adverse outcomes are needed. By individual-level linkage of nationwide registries, we identified all patients discharged from hospitals with AF in Denmark between 1997 and 2011. Patients with available serum creatinine tests were categorized according to the estimated glomerular filtration rate (eGFR). Time in therapeutic range (TTR) was calculated using the Rosendaal method. The risk of stroke and bleeding was estimated using multivariable Cox regression analyses with eGFR and TTR estimated time dependently throughout follow-up. We identified 10,423 warfarin-treated AF patients with available international normalized ratio and creatinine tests; 5,527 with eGFR > 60 mL/min/1.73 m2, 4,524 with eGFR 30–60 mL/min/1.73 m2 and 372 with eGFR < 30 mL/min/1.73 m2. Median TTR was 66.7, 61.2 and 49.7% in patients with eGFR > 60, 30–59 and <30 mL/min/1.73 m2, respectively. A TTR < 70% was associated with a higher risk of stroke/thromboembolism (hazard ratio [HR]: 1.39; 95% confidence interval [CI]: 1.20–1.60) and bleeding (HR: 1.22; 95% CI: 1.05–1.42) among patients with eGFR of 30 to 59 and a trend towards higher risk of stroke/thromboembolism (HR: 1.24; 95% CI: 0.86–1.80) and bleeding (HR: 1.17; 95% CI: 0.83–1.65) among patients with eGFR < 30 mL/min/1.73 m2. In conclusion, warfarin-treated AF patients with reduced renal function have suboptimal anticoagulation control which was related to the risk of adverse outcomes.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Creatinine; Denmark; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Kidney; Male; Middle Aged; Registries; Retrospective Studies; Risk; Stroke; Thromboembolism; Warfarin

Current methods for prospective drug safety monitoring focus on determining whether and when to generate safety alerts indicating that a new drug may be less safe than a comparator. Approaches are needed to develop safety thresholds that can be used to define whether a new drug is no less than or equally safe as the comparator.. Our aim is to develop a framework for determining which safety statements can be made about a new drug and when they can be made during prospective monitoring.. We developed a two-pronged approach to establish safety thresholds for active monitoring. First, we adapted concepts from setting margins in non-inferiority (NI) trials ("NI approach"). Second, we summarized NI margins used in published randomized trials and reviewed publicly available data from the US FDA's website to identify the type and magnitude of evidence used in regulatory decisions involving withdrawals and black box warnings between 2009 and 2013 ("benchmark approach"). We applied the framework to a case study of dabigatran versus warfarin and major bleed.. We provide formulas on both risk ratio and risk difference scales for the NI approach that are analogous to threshold setting in NI trials but based on point estimates and using a maximum tolerable increase rather than a preservation factor. Using this approach, we established a safety threshold for the dabigatran case study that was within range of the findings from the benchmark approach (1.18 to 7.30). Comparing the safety threshold with post-approval studies of dabigatran versus warfarin indicated that no safety statement can be made.. The proposed framework expands the safety statements that can be made in current prospective drug safety monitoring systems. Copyright © 2015 John Wiley & Sons, Ltd.

Topics: Anticoagulants; Benchmarking; Clinical Trials as Topic; Dabigatran; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Pharmacoepidemiology; Product Surveillance, Postmarketing; Risk; Warfarin

Heart failure (HF) patients are at high risk of having drug-related problems (DRPs). We aim to describe the frequency, types, and temporal occurrence of DRPs in Taiwanese HF outpatients receiving case management.. In this study, we included 141 patients from HF clinics in three hospitals in Taiwan from October 2008 to December 2010. Nurse case managers at each of the participating sites registered case report forms (CRFs) for patients during clinic visits. DRPs were classified using the Pharmaceutical Care Network Europe Foundation (PCNE) classification system and documented by pharmacists after reviewing CRFs and participating in multidisciplinary team discussions.. For 141 clinic participants, the average duration of medication use was 17 months, and 796 DRPs were reported. The DRPs most frequently recorded were the need for laboratory tests (32.7% of total DRPs), followed by potential interaction (29.6%), nonallergic side effects (13.3%), and insufficient awareness of health and disease (9.5%). The drugs most frequently causing a DRP were angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers, diuretics, warfarin, spironolactone, and β-blockers. The incidence rates of total DRPs was maximal during the initial 3 months of medication treatment, whereas the incidence rates of each category of DRPs showed multiform changes over time among various drug classes.. In Taiwan where the clinical pharmacist system is not well organized, HF outpatients still had a high prevalence of DRPs despite intensive monitoring by nurse case managers. Clinical pharmacists play critical roles in detecting potential DRPs during long-term medication treatment for this population.

Topics: Adrenergic beta-Antagonists; Aged; Ambulatory Care; Angiotensin-Converting Enzyme Inhibitors; Case Management; Diuretics; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Heart Failure; Humans; Male; Middle Aged; Outpatients; Prospective Studies; Spironolactone; Taiwan; Warfarin

Our purpose was to quantify missing baseline laboratory results, assess predictors of missingness, and examine performance of missing data methods.. Using the Mini-Sentinel Distributed Database from three sites, we selected three exposure-outcome scenarios with laboratory results as baseline confounders. We compared hazard ratios (HRs) or risk differences (RDs) and 95% confidence intervals (CIs) from models that omitted laboratory results, included only available results (complete cases), and included results after applying missing data methods (multiple imputation [MI] regression, MI predictive mean matching [PMM] indicator).. Scenario 1 considered glucose among second-generation antipsychotic users and diabetes. Across sites, glucose was available for 27.7-58.9%. Results differed between complete case and missing data models (e.g., olanzapine: HR 0.92 [CI 0.73, 1.12] vs 1.02 [0.90, 1.16]). Across-site models employing different MI approaches provided similar HR and CI; site-specific models provided differing estimates. Scenario 2 evaluated creatinine among individuals starting high versus low dose lisinopril and hyperkalemia. Creatinine availability: 44.5-79.0%. Results differed between complete case and missing data models (e.g., HR 0.84 [CI 0.77, 0.92] vs. 0.88 [0.83, 0.94]). HR and CI were identical across MI methods. Scenario 3 examined international normalized ratio (INR) among warfarin users starting interacting versus noninteracting antimicrobials and bleeding. INR availability: 20.0-92.9%. Results differed between ignoring INR versus including INR using missing data methods (e.g., RD 0.05 [CI -0.03, 0.13] vs 0.09 [0.00, 0.18]). Indicator and PMM methods gave similar estimates.. Multi-site studies must consider site variability in missing data. Different missing data methods performed similarly. Copyright © 2016 John Wiley & Sons, Ltd.

Topics: Antipsychotic Agents; Clinical Laboratory Techniques; Confounding Factors, Epidemiologic; Creatinine; Data Interpretation, Statistical; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Female; Glucose; Humans; International Normalized Ratio; Lisinopril; Male; Proportional Hazards Models; Regression Analysis; Warfarin

Background Drug-drug interactions in patients taking warfarin may contribute to a higher risk of adverse events. Objective To identify and evaluate the prevalence and characteristics of potential DDIs with warfarin. Methods A cross-sectional study was performed in a Brazilian tertiary hospital. The electronic prescriptions of the patients receiving warfarin between January 2004 and December 2010 were analyzed. Socio-demographic, clinical, and therapeutic variables were collected. Warfarin drug-drug interactions were classified as either risk A, B, C, D, or X according to the Lexi-Interact™ Online database. Results A total of 3048 patients were identified who were prescribed warfarin. Of the 154,161 total drug prescriptions issued, 42,120 (27.3 %) were for warfarin. Evaluation of the prescriptions showed that 63.1 and 0.1 % of patients received concomitant drugs classified as having class D or X risk. It was found that 20,539 (48.7 %) prescriptions had at least one drug with a D or X risk. Patients were prescribed an average of 1.4 (±0.4) concomitant medications with a class D or X warfarin-DDI risk, the most frequent being acetylsalicylic acid and amiodarone. Conclusion The results demonstrate a high prevalence of concomitant drug prescriptions with the potential for clinically relevant DDIs with warfarin, the most frequent being acetylsalicylic acid and amiodarone.

Topics: Adult; Aged; Amiodarone; Anticoagulants; Aspirin; Brazil; Cross-Sectional Studies; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hospitalization; Humans; Male; Middle Aged; Tertiary Care Centers; Warfarin

Topics: Antidepressive Agents; Child; Dideoxynucleosides; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Genetic Testing; HIV Infections; HLA-B Antigens; Humans; Male; Mercaptopurine; Pharmacogenetics; Precision Medicine; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Primaquine; Purine-Pyrimidine Metabolism, Inborn Errors; Succinylcholine; Warfarin

  To avoid major bleeding events in warfarin and S-1 combination therapy, PT-INR levels should be monitored frequently to allow for precise adjustments of the warfarin dose and to verify any side effects reported by the patient. We therefore developed a support system where outpatients obtain a home-measured PT-INR value using the CoaguChek(®) system and submit it along with details of any side effects to us via the Internet using their mobile phone. A 59-year-old man was started on warfarin (1.5 mg/d) and S-1 (100 mg/d), a combination preparation of tegafur, gimeracil, and oteracil potassium, to treat cholangiocarcinoma. The patient sent his data to the hospital pharmacist every two days after starting S-1 therapy. When the PT-INR was outside the target range of 1.5-2.7, the pharmacist, after consulting the physician, instructed the patient to change his warfarin dose by 0.5 mg. On day 24 after starting S-1, PT-INR had increased from 1.6 to 2.8, so the dose was decreased by 0.5 mg. Thereafter, the dose was adjusted by 0.5-1.0 mg during the observation period so that the patient was able to maintain the therapeutic range approximately 90% of the time. We anticipate this system can be applied to S-1 which interact with warfarin, thereby enabling safer anticoagulation therapy.

Topics: Cholangiocarcinoma; Drug Combinations; Drug Interactions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Humans; International Normalized Ratio; Internet; Male; Middle Aged; Monitoring, Physiologic; Oxonic Acid; Prothrombin Time; Tegafur; Warfarin

Proton pump inhibitors (PPIs) have been suggested to increase the effect of warfarin, and clinical guidelines recommend careful monitoring of international normalized ratio (INR) when initiating PPI among warfarin users. However, this drug-drug interaction is sparsely investigated in a clinical setting. The aim was to assess whether initiation of PPI treatment among users of warfarin leads to increased INR values.. The study was an observational self-controlled study from 1998 to 2012 leveraging data on INR measurements on patients treated with warfarin from primary care and outpatient clinics and their use of prescription drugs. Data were analyzed in 2015. We assessed INR, warfarin dose, and dose/INR ratio before and after initiating PPI treatment using the paired student's t-test.. We identified 305 warfarin users initiating treatment with PPIs. The median age was 71 years (interquartile range 63-78 years), and 64% were men. The mean INR in the 70 days prior to PPI initiation was 2.6 (95%CI 2.5-2.8) and 2.6 (95%CI 2.5-2.7) in the period 1-3 weeks after PPI initiation (p = 0.67). Further, neither mean warfarin dose nor the dose/INR ratios were significantly different before and after PPI initiation. Sensitivity analyses revealed no differences among individual PPIs.. We found no evidence of a clinically meaningful drug-drug interaction between PPIs and warfarin in a Northern European patient population of unselected patients from an everyday outpatient and primary care clinical setting. Thus, we do not support the recommendation to "cautiously monitor" users of warfarin initiating PPI treatment.

Topics: Aged; Anticoagulants; Denmark; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Humans; International Normalized Ratio; Male; Middle Aged; Practice Patterns, Physicians'; Proton Pump Inhibitors; Warfarin

To explore if sex differences are found in spontaneously reported adverse events for clopidogrel, low-dose aspirin and warfarin treatment in routine care.. A cross-sectional analysis combining data on bleeding events from the Swedish Spontaneous Adverse Drug Event Reporting System (SWEDIS) with data from the National Prescribed Drug register. Bleeding event reports from 1999 to 2010 and 2005 to 2010 were adjusted to the number of prescriptions and the number of exposed patients respectively among women and men. Co-medication and co-prescription were analysed.. More men were dispensed clopidogrel although the reported bleeding event risk after adjustment for number of patients exposed was higher in women (RR 1.40; 95 % CI, 1.00-1.96). The difference disappeared when adjusting for the number of prescriptions (RR 0.99; 95 % CI, 0.71-1.39). The reported bleeding event risk with low-dose aspirin was lower in women, adjusted for patients exposed (RR 0.80; 95 % CI, 0.66-0.97). For warfarin, no sex difference in bleeding event reports could be found (RR 1.01; 95 % CI, 0.87-1.17).. This ecological comparison of bleeding reports and dispensed prescriptions showed a signal towards a higher prevalence of bleeding reports in women on clopidogrel treatment while the opposite was found for low-dose aspirin. For warfarin, no significant sex difference was seen regarding bleeding event reports, suggesting individualised dosing being an important factor. Men were more commonly prescribed antithrombotic combinations, and this was reflected by a larger proportion of bleeding reports including more than one antithrombotic agent.

Topics: Adolescent; Adult; Adverse Drug Reaction Reporting Systems; Aged; Aspirin; Child; Child, Preschool; Clopidogrel; Drug-Related Side Effects and Adverse Reactions; Female; Fibrinolytic Agents; Hemorrhage; Humans; Infant; Infant, Newborn; Male; Middle Aged; Practice Patterns, Physicians'; Risk; Sex Factors; Sweden; Ticlopidine; Warfarin; Young Adult

Two variants in the gene encoding the cytochrome P450 2C9 enzyme (CYP2C9) are considered the most significant genetic risk factors associated with bleeding after warfarin prescription. A variant in the vitamin K epoxide reductase (VKORC1) has been also associated by several studies with warfarin response. Another variant in the P450 3A5 enzyme (CYP3A5) gene is known to affect the metabolism of many drugs, including tacrolimus.. We conducted a population genetic study in 148 unrelated healthy Greek-Cypriot volunteers (through PCR-RFLP assays), in order to determine the frequencies of the above pharmacogenetics variants and to compare allele frequencies with those in other major ethnic groups. The allele frequencies of CYP2C9*2, CYP2C9*3 and CYP3A5*3 were found to be 0.162, 0.112 and 0.943 respectively, whereas VKORC1 - 1639A was 0.534. The latter frequency differs significantly when compared with Caucasians, Asians and Africans (p < 0.001) and is still significant when compared with the geographically and culturally closely related to Greek-Cypriots, Hellenes of Greece (p = 0.01). Interestingly ~18% of our population are carriers of four or three risk alleles regarding warfarin sensitivity, therefore they have a high predisposition for bleeding after taking high or even normal warfarin doses.. Our data show no significant difference in the frequency of CYP2C9 and CYP3A5 allelic variants when compared to the Caucasian population, but differ significantly when compared with Africans and Asians (p < 0.001). Also, the frequency of variant VKORC1 - 1639A differs between Greek-Cypriots and every other population we compared. Finally, about 1/5 Greek-Cypriots carry three or four risk alleles and ~50% of them carry at least two independent risk alleles regarding warfarin sensitivity, a potentially high risk for over-anticoagulation.

Topics: Adult; Aryl Hydrocarbon Hydroxylases; Cyprus; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP3A; Drug-Related Side Effects and Adverse Reactions; Gene Frequency; Genetic Predisposition to Disease; Genotype; Greece; Humans; Male; Polymerase Chain Reaction; Polymorphism, Genetic; Polymorphism, Restriction Fragment Length; Risk Factors; Tacrolimus; Vitamin K Epoxide Reductases; Warfarin; Young Adult

Patients in nursing homes are often treated with many drugs concurrently (polypharmacy), which increases the risk of drug-drug interactions. The purpose of this study was to assess the incidence of such interactions in nursing home patients.. The study was based on medication lists collected from all nursing home patients in Trondheim Municipality in the course of one day in 2010. Data from the medication lists was linked to the Norwegian interaction database, Druid.. The study included 1241 nursing home patients. Patients used an average of 9.8 drugs regularly or as needed, with a variation of from 0 to 30. In all, 15 patients (1.2%) used drug combinations that are classified in Druid as «should not be combined», while 592 (47.7%) used combinations classified as «take precautions». There was a clear relationship between the number of drugs prescribed and the risk of interactions. The three most common drug combinations in the group «should not be combined» were warfarin and non-steroidal anti-inflammatory drugs, clopidogrel and proton pump inhibitors, and anti-Parkinson medication and dopamine antagonists.. The incidence of serious drug-drug interactions among nursing home patients in Trondheim Municipality is low. Polypharmacy is widespread, and the incidence of drug interactions where precautions should be taken is high. As nursing home patients are a vulnerable group with respect to drug interactions, the risk of interactions should be carefully considered when treatment with a new drug is started.

Topics: Anti-Inflammatory Agents, Non-Steroidal; Antiparkinson Agents; Clopidogrel; Databases, Factual; Dopamine Antagonists; Drug Interactions; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Humans; Nursing Homes; Platelet Aggregation Inhibitors; Polypharmacy; Proton Pump Inhibitors; Ticlopidine; Warfarin

Topics: Anticoagulants; Contraindications; Diet; Drug-Related Side Effects and Adverse Reactions; Herb-Drug Interactions; Humans; Vegetables; Warfarin

The aims of this study are to evaluate prevalence and characteristics of adverse drug reactions (ADRs) and to evaluate the potential contribution of specific medications, therapeutic categories and drug-drug interactions (DDIs) in older adults.. All ADR reporting forms of persons aged 65+ years collected by the pharmacovigilance of one of the main hospitals in Italy during 2013 were evaluated. DDIs were analysed by a computerized prescription system (INTERCheck) and based on the interactions' database managed by the Istituto di Ricerche Farmacologiche Mario Negri. DDIs were classified according to their clinical relevance as contraindicated, major, and moderate.. Amongst all the ADR reporting forms (n=1014) collected during 2013, 343 affected older adults. The most frequent ADRs were: haemorrhages (n=122, 35.5%), allergic reactions (n=56, 16.3%), and elevated International Normalized Ratio (INR>6, n=54, 15.7%). The specific medications that contributed to ADRs were warfarin (42.5%), acenocumarol (9%), and allopurinol (8.5%); while the therapeutic categories were haematological agents (67%) and proton pump inhibitors (13%). A total of 912 DDIs were found; one third of them were contraindicated or major and 31.5% of them potentially contributed to ADRs; of these, the most frequent were: warfarin and heparin (contraindicated, n=5); warfarin and a statin (major, n=38); warfarin and a proton pump inhibitor (moderate, n=40). At least one DDI contributed to 66 haemorrhages out of 122 (54%) and to 41 elevated INR out of 54 (76%).. DDIs significantly contribute to the onset of ADRs in older adults and intervention programmes, e.g., the employment of a computerized system, may reduce the burden of iatrogenic illnesses in the elderly.

Topics: Acenocoumarol; Age Factors; Aged; Allopurinol; Drug Hypersensitivity; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Hematologic Agents; Hemorrhage; Humans; International Normalized Ratio; Italy; Male; Prevalence; Proton Pump Inhibitors; Warfarin

Topics: Drug-Related Side Effects and Adverse Reactions; Humans; Neoplasms; Periodicals as Topic; Pharmacogenetics; Warfarin

Topics: Anticoagulants; Blood Coagulation; Blood Coagulation Factors; Clinical Protocols; Coagulants; Dose-Response Relationship, Drug; Drug-Related Side Effects and Adverse Reactions; Hemorrhage; Humans; International Normalized Ratio; Practice Guidelines as Topic; Risk Assessment; United Kingdom; Warfarin

Drug-induced liver injury is the most common cause of market withdrawal of pharmaceuticals, and thus, there is considerable need for better prediction models for DILI early in drug discovery. We present a study involving 223 marketed drugs (51% associated with clinical hepatotoxicity; 49% non-hepatotoxic) to assess the concordance of in vitro bioactivation data with clinical hepatotoxicity and have used these data to develop a decision tree to help reduce late-stage candidate attrition. Data to assess P450 metabolism-dependent inhibition (MDI) for all common drug-metabolizing P450 enzymes were generated for 179 of these compounds, GSH adduct data generated for 190 compounds, covalent binding data obtained for 53 compounds, and clinical dose data obtained for all compounds. Individual data for all 223 compounds are presented here and interrogated to determine what level of an alert to consider termination of a compound. The analysis showed that 76% of drugs with a daily dose of <100 mg were non-hepatotoxic (p < 0.0001). Drugs with a daily dose of ≥100 mg or with GSH adduct formation, marked P450 MDI, or covalent binding ≥200 pmol eq/mg protein tended to be hepatotoxic (∼ 65% in each case). Combining dose with each bioactivation assay increased this association significantly (80-100%, p < 0.0001). These analyses were then used to develop the decision tree and the tree tested using 196 of the compounds with sufficient data (49% hepatotoxic; 51% non-hepatotoxic). The results of these outcome analyses demonstrated the utility of the tree in selectively terminating hepatotoxic compounds early; 45% of the hepatotoxic compounds evaluated using the tree were recommended for termination before candidate selection, whereas only 10% of the non-hepatotoxic compounds were recommended for termination. An independent set of 10 GSK compounds with known clinical hepatotoxicity status were also assessed using the tree, with similar results.

Topics: Chemical and Drug Induced Liver Injury; Cytochrome P-450 Enzyme Inhibitors; Cytochrome P-450 Enzyme System; Decision Trees; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Glutathione; Humans; Liver; Pharmaceutical Preparations; Protein Binding

Safety of anticoagulant administration has been a primary concern of the Joint Commission on Accreditation of Healthcare Organizations. Among all anticoagulants, warfarin has long been listed among the top ten drugs causing adverse drug events. Due to narrow therapeutic range and significant side effects, warfarin dosage determination becomes a challenging task in clinical practice. For superior clinical decision making, this study attempts to build a warfarin dosage prediction model utilizing a number of supervised learning techniques.. The data consists of complete historical records of 587 Taiwan clinical cases who received warfarin treatment as well as warfarin dose adjustment. A number of supervised learning techniques were investigated, including multilayer perceptron, model tree, k nearest neighbors, and support vector regression (SVR). To achieve higher prediction accuracy, we further consider both homogeneous and heterogeneous ensembles (i.e., bagging and voting). For performance evaluation, the initial dose of warfarin prescribed by clinicians is established as the baseline. The mean absolute error (MAE) and standard deviation of errors (σ(E)) are considered as evaluation indicators.. The overall evaluation results show that all of the learning based systems are significantly more accurate than the baseline (MAE=0.394, σ(E)=0.558). Among all prediction models, both Bagged Voting (MAE=0.210, σ(E)=0.357) with four classifiers and Bagged SVR (MAE=0.210, σ(E)=0.366) are suggested as the two most effective prediction models due to their lower MAE and σ(E).. The investigated models can not only facilitate clinicians in dosage decision-making, but also help reduce patient risk from adverse drug events.

Topics: Algorithms; Anticoagulants; Databases, Factual; Decision Support Techniques; Drug-Related Side Effects and Adverse Reactions; Humans; Support Vector Machine; Taiwan; Warfarin

The prevalence and etiology of occult bleeding among patients on warfarin who are screened systematically for new anemia is largely unknown. We aimed to estimate the usefulness of following hemoglobin and mean red cell volume (MCV) with INR in order to screen for developing anemia as an indicator of occult bleeding.. All patients on warfarin controlled at our institution had measurements of complete blood count (CBC) with INR during 18 months. Patients who fell>25 g/L and/or decrease of MCV over 5 fL or MCV<80 fL were contacted with instructions to undergo evaluation of anemia.. Overall 3218 patients on warfarin were monitored at our institution and 442 (13.7%) had anemia and 235 (7.3%) had unexplained anemia. A total of 163/235 (69%) who were notified contacted their doctors and 82/163 (50%) were referred for investigation with upper and/or lower endoscopies. Gastrointestinal malignancies were found in 11 patients (10 colorectal cancers, 1 esophageal) and pre-cancerous lesions among 14 other patients. Additional 25/82 patients (30%) had upper and/or lower bleeding lesions such as ulcers and angiodysplasia. Based on 3669 years of observation, 73 patients needed to be screened for one year in order to identify one gastrointestinal lesion causing occult bleeding.. Thirty percent of those endoscoped had malignant or pre-malignant diseases. Regular measurement of CBC concomitantly with INR in patients on warfarin therapy led to detection of otherwise asymptomatic diseases in a significant proportion of patients and might lead to earlier diagnosis of malignant and premalignant disease.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Anemia; Anticoagulants; Blood Cell Count; Child; Drug-Related Side Effects and Adverse Reactions; Female; Gastrointestinal Neoplasms; Humans; Iceland; Incidence; International Normalized Ratio; Male; Mass Screening; Middle Aged; Precancerous Conditions; Prevalence; Risk Assessment; Warfarin; Young Adult

As electronic health records (EHRs) become widely adopted, alerts and reminders can improve medication safety, but excessive alerts may irritate or overwhelm clinicians, thereby reducing their effectiveness. We developed a novel "stealth" alert in an EHR to improve anticoagulation monitoring for patients prescribed a medication that could interact with warfarin. Instead of alerting the prescribing provider, the system notified a multidisciplinary anticoagulation management service, so that the prescribing clinicians never saw the alerts. We aimed to determine whether these "stealth" alerts increased the frequency of anticoagulation monitoring following the co-prescription of warfarin and a potentially interacting medication.. We conducted a pre-post intervention study, analyzed using an interrupted time-series, within a large, multispecialty group practice that uses a common EHR. The study included a 12-month period preceding the intervention, a 2-month period during intervention implementation, and a 6-month post-intervention period. The primary outcome measure was the proportion of patients completing anticoagulation monitoring within 5 days of a new co-prescribing event.. Prior to implementation of the stealth alert, 34 % of patients completed anticoagulation monitoring within 5 days after the prescription of a medication with a potential warfarin interaction. After implementation of the alert, 39 % completed testing within 5 days (odds ratio 1.24, 95 % confidence interval 1.12-1.37).. Stealth alerts increased the proportion of patients who underwent anticoagulation monitoring following the prescription of a medication that could potentially interact with warfarin. This team-based approach to clinical-decision support directs alerts away from prescribing clinicians and toward individuals who can directly implement them.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Confidence Intervals; Cross-Sectional Studies; Drug Interactions; Drug Monitoring; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Male; Medical Order Entry Systems; Middle Aged; Odds Ratio; Practice Patterns, Physicians'; Quality Improvement; United States; Warfarin; Young Adult

Drug-induced liver injury (DILI) is a leading cause of drugs failing during clinical trials and being withdrawn from the market. Comparative analysis of drugs based on their DILI potential is an effective approach to discover key DILI mechanisms and risk factors. However, assessing the DILI potential of a drug is a challenge with no existing consensus methods. We proposed a systematic classification scheme using FDA-approved drug labeling to assess the DILI potential of drugs, which yielded a benchmark dataset with 287 drugs representing a wide range of therapeutic categories and daily dosage amounts. The method is transparent and reproducible with a potential to serve as a common practice to study the DILI of marketed drugs for supporting drug discovery and biomarker development.

Topics: Animals; Benchmarking; Biomarkers, Pharmacological; Chemical and Drug Induced Liver Injury; Drug Design; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmaceutical Preparations; Reproducibility of Results; United States; United States Food and Drug Administration

Drug-induced liver injury (DILI) is a significant concern in drug development due to the poor concordance between preclinical and clinical findings of liver toxicity. We hypothesized that the DILI types (hepatotoxic side effects) seen in the clinic can be translated into the development of predictive in silico models for use in the drug discovery phase. We identified 13 hepatotoxic side effects with high accuracy for classifying marketed drugs for their DILI potential. We then developed in silico predictive models for each of these 13 side effects, which were further combined to construct a DILI prediction system (DILIps). The DILIps yielded 60-70% prediction accuracy for three independent validation sets. To enhance the confidence for identification of drugs that cause severe DILI in humans, the "Rule of Three" was developed in DILIps by using a consensus strategy based on 13 models. This gave high positive predictive value (91%) when applied to an external dataset containing 206 drugs from three independent literature datasets. Using the DILIps, we screened all the drugs in DrugBank and investigated their DILI potential in terms of protein targets and therapeutic categories through network modeling. We demonstrated that two therapeutic categories, anti-infectives for systemic use and musculoskeletal system drugs, were enriched for DILI, which is consistent with current knowledge. We also identified protein targets and pathways that are related to drugs that cause DILI by using pathway analysis and co-occurrence text mining. While marketed drugs were the focus of this study, the DILIps has a potential as an evaluation tool to screen and prioritize new drug candidates or chemicals, such as environmental chemicals, to avoid those that might cause liver toxicity. We expect that the methodology can be also applied to other drug safety endpoints, such as renal or cardiovascular toxicity.

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Chemical and Drug Induced Liver Injury; Databases, Factual; Drug-Related Side Effects and Adverse Reactions; Humans; Liver; Models, Biological; Predictive Value of Tests

Topics: Anticoagulants; Aryl Hydrocarbon Hydroxylases; Cytochrome P-450 CYP2C9; Drug-Related Side Effects and Adverse Reactions; Genetic Testing; Genotype; Hemorrhage; Humans; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Genetic; Vitamin K Epoxide Reductases; Warfarin

Therapeutic (international normalized ratio, INR 2.0-3.5) oral anticoagulation (TOAC) is assumed to increase perioperative bleeding complications and a standard recommendation is to discontinue warfarin before coronary bypass grafting (CABG).. To assess the safety of TOAC we retrospectively analyzed consecutive patients (n=270) with long-term warfarin therapy referred for CABG in two centers where TOAC strategy is employed. The main in-hospital outcomes of interest were death, stroke, acute myocardial infarction, new onset renal failure, resternotomy, and their composite. In the TOAC group of 103 patients CABG was performed during therapeutic oral anticoagulation and in the control group (81 patients) preoperative INR was lowered to a subtherapeutic (≤1.5) level.. The patients in TOAC group were more often operated on an emergency basis (p=0.02) and their EuroSCORE was higher (p=0.02). There were no significant differences in the major outcome events or their composite (17.5 vs. 11.1%, p=0.30) between the groups. Patients in the TOAC group had more postoperative blood loss (941±615 vs. 754±610 ml, p<0.01) and received more fresh frozen plasma (2.8±3.0 vs. 1.3±2.4 units, p<0.001), but transfused red blood cells (2.1±2.8 vs. 2.1±3.4 units) were comparable in the groups. Preoperative clopidogrel (OR 4.8, 95% CI 1.4-16.2, p=0.01) and enoxaparin therapy (OR 2.6, 95% CI 1.1-6.5, p=0.04) were the only significant independent predictors for any major adverse event.. Our study suggests that CABG is a safe procedure during TOAC with no excess bleeding or major complications. Prospective trials are needed to confirm this observation.

Topics: Aged; Anticoagulants; Blood Loss, Surgical; Case-Control Studies; Coronary Artery Bypass; Drug-Related Side Effects and Adverse Reactions; Enoxaparin; Female; Humans; International Normalized Ratio; Intraoperative Complications; Male; Middle Aged; Retrospective Studies; Warfarin

This represents the fifth article in the series on yearly updates of hot topics in long term care.

Topics: Anti-Ulcer Agents; Anticoagulants; Atrial Fibrillation; Clopidogrel; Clostridioides difficile; Delirium; Diabetes Complications; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Female; Fractures, Bone; Geriatric Nursing; Humans; Male; Nursing Homes; Omeprazole; Osteoporosis; Peptic Ulcer; Platelet Aggregation Inhibitors; Pneumonia, Bacterial; Polypharmacy; Proton Pump Inhibitors; Risk Factors; Ticlopidine; Warfarin; Weight Loss

Warfarin management in the elderly population is complex as medicines prescribed for concomitant diseases may further increase the risk of major bleeding associated with warfarin use. We aimed to quantify the excess risk of bleeding-related hospitalisation when warfarin was co-dispensed with potentially interacting medicines.. A retrospective cohort study was undertaken over a 4-year period from July 2002 to June 2006 to examine bleeding risk associated with medications co-administered in patients taking warfarin using an administrative claims database from the Australian Department of Veterans' Affairs. All veterans aged 65 years and over who were new users of warfarin were followed until death or study end. Risk of bleeding was assessed using a Poisson GEE model adjusting for age, gender, socioeconomic status, co-morbidity index, previous bleeding related hospitalisations and indicators of health service use.. Overall, 17661 veterans who used warfarin at any time during the study period were included. The overall incidence rate of bleeding-related hospitalisations was 4.1 (95% CI 3.7-4.6) per 100 person-years in veterans who were not receiving potentially interacting medicines. Bleeding-related hospitalisation rates were significantly increased when warfarin was co-prescribed with low-dose aspirin (Adjusted rate ratio (AdjRR) 1.44, 95% CI 1.00-2.07), clopidogrel (AdjRR 2.23, 95% CI 1.48–3.36), clopidogrel with aspirin (AdjRR 3.44, 95% CI 1.28-9.23), amiodarone (AdjRR 3.33, 95% CI 1.38–8.00) and antibiotics (AdjRR 2.34, 95% CI 1.55-3.54).. Models assessing bleeding risk with warfarin should take account of the range of potentially harmful medicine combinations used in elderly people with comorbid conditions.

Topics: Aged; Aged, 80 and over; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Atrial Fibrillation; Cohort Studies; Databases, Factual; Drug Interactions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Female; Hemorrhage; Humans; Male; Platelet Aggregation Inhibitors; Retrospective Studies; Risk; Risk Factors; Warfarin

Topics: Anticoagulants; Chest Pain; Coloring Agents; Drug Hypersensitivity; Drug-Related Side Effects and Adverse Reactions; Humans; Male; Middle Aged; Skin Diseases; Warfarin

Clopidogrel, a new antiplatelet agent that irreversibly inhibits platelet aggregation, is widely used today. This prospective work was conducted to evaluate the safety of performing skin surgery on patients taking clopidogrel. Patients undergoing surgery for excision of skin or subcutaneous lesions under local anesthesia taking clopidogrel were the study group. The control group comprised 2073 historical patients who had undergone a similar procedure. Data collected included: age, sex, past medical history, medications, and late complications. Follow-up was done at 1 to 2 weeks and 3 to 6 months. There were 32 patients on clopidogrel, having 38 lesions removed. Of these, seven patients were on aspirin and clopidogrel combined. The groups taking clopidogrel, aspirin, and warfarin had significantly more males, were older, and had significantly more comorbid medical conditions. There was no significant difference in the incidence of any of the complications in any of the groups. This study shows that patients taking clopidogrel before skin surgery, though older and with more associated medical conditions, do not experience a greater rate of complications. We conclude that patients undergoing minor excisional cutaneous surgery should continue taking clopidogrel because there is no apparent risk for increased complications when good meticulous surgical techniques are used.

Topics: Aged; Anticoagulants; Aspirin; Case-Control Studies; Clopidogrel; Dermatologic Surgical Procedures; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Erythema; Female; Follow-Up Studies; Hematoma; Humans; Male; Platelet Aggregation Inhibitors; Postoperative Complications; Surgical Wound Dehiscence; Surgical Wound Infection; Ticlopidine; Warfarin

The 2009 Golden Helix Symposium on Pharmacogenomics and Personalized medicine was held in Athens, Greece, where approximately 150 participants from 21 countries were updated on recent developments in the fields of pharmacogenetics and pharmacogenomics. The meeting was supported by ten corporate entities, of which three were major pharmaceutical and two were technology companies. It was endorsed by the University of Chicago and partly funded by the University of Patras. Here, we report some highlights of this meeting.

Topics: Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Genetic Variation; Humans; Mental Disorders; Nervous System Diseases; Pharmacogenetics; Polymorphism, Single Nucleotide; Precision Medicine; Warfarin

Currently, pharmaceutical companies are reluctant to introduce pharmacogenomics (PGx) in their practice, since cost-benefit of PGx is obscure and methodology to use PGx in drug development has not been fully established yet. The purpose of this study is to investigate advantages obtained by introducing PGx in clinical trials. Particularly, taking Warfarin as an example, we investigate benefits of Enrichment effect that raises response rate of the drug by PGx. When response rate is raised by only 5%, cost of a clinical trial can be reduced to about 40% of a conventional clinical trial. Furthermore, since period necessary for a trial also can be reduced, development period can be shortened by about 750 days. In summary, PGx enables earlier launch of a drug with less cost, representing benefit to pharmaceutical companies, patients and public as a whole.

Topics: Anticoagulants; Clinical Trials as Topic; Cost-Benefit Analysis; Drug-Related Side Effects and Adverse Reactions; Humans; Mixed Function Oxygenases; Pharmacogenetics; Polymorphism, Single Nucleotide; Precision Medicine; Vitamin K Epoxide Reductases; Warfarin

Anticoagulation may in the future become a therapeutic option for the prevention of liver fibrosis, such as due to recurrent hepatitis C virus infection after liver transplantation. Currently, there are other indications for anticoagulation after liver transplantation but no data regarding its safety. The objective of the study was to audit the safety of anticoagulation after liver transplantation. Liver transplant recipients receiving anticoagulation postoperatively were compared with a matched control group with respect to bleeding complications and postoperative course. Anticoagulation did not increase the risk of bleeding complications after liver transplantation. On the basis of safety, it appears feasible to use anticoagulation in trials to assess prevention of liver fibrosis.

Topics: Adolescent; Adult; Anticoagulants; Data Collection; Drug-Related Side Effects and Adverse Reactions; Female; Fibrosis; Hemorrhage; Humans; Incidence; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Warfarin; Young Adult

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

The chemical space of registered oral drugs was explored for inhibitors of the human multidrug-resistance associated protein 2 (MRP2; ABCC2), using a data set of 191 structurally diverse drugs and drug-like compounds. The data set included a new reference set of 75 compounds, for studies of hepatic drug interactions with transport proteins, CYP enzymes, and compounds associated with liver toxicity. The inhibition of MRP2-mediated transport of estradiol-17beta-D-glucuronide was studied in inverted membrane vesicles from Sf9 cells overexpressing human MRP2. A total of 27 previously unknown MRP2 inhibitors were identified, and the results indicate an overlapping but narrower inhibitor space for MRP2 compared with the two other major ABC efflux transporters P-gp (ABCB1) and BCRP (ABCG2). In addition, 13 compounds were shown to stimulate the transport of estradiol-17beta-D-glucuronide. The experimental results were used to develop a computational model able to discriminate inhibitors from noninhibitors according to their molecular structure, resulting in a predictive power of 86% for the training set and 72% for the test set. The inhibitors were in general larger and more lipophilic and presented a higher aromaticity than the noninhibitors. The developed computational model is applicable in an early stage of the drug discovery process and is proposed as a tool for prediction of MRP2-mediated hepatic drug interactions and toxicity.

Topics: Administration, Oral; Animals; Antineoplastic Agents; Antipsychotic Agents; Antiviral Agents; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; ATP Binding Cassette Transporter, Subfamily G, Member 2; ATP-Binding Cassette Transporters; Biological Transport; Cell Line; Computer Simulation; Cytochrome P-450 Enzyme System; Drug-Related Side Effects and Adverse Reactions; Estradiol; Humans; Insecta; Liver; Models, Molecular; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neoplasm Proteins; Pharmaceutical Preparations; Pharmacology; Structure-Activity Relationship

Topics: Aged, 80 and over; Anticoagulants; Continuity of Patient Care; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Female; Humans; International Normalized Ratio; Medication Errors; Nurse Practitioners; Patient Education as Topic; Perioperative Care; Primary Health Care; Risk Factors; Warfarin

The Threats to Australian Patient Safety (TAPS) study collected 648 anonymous reports about threats to patient safety from a representative random sample of Australian general practitioners. These contained any events the GPs felt should not have happened, and would not want to happen again, regardless of who was at fault or the outcome of the event. This series of articles presents clinical lessons resulting from the TAPS study.

Topics: Drug-Related Side Effects and Adverse Reactions; Female; Humans; Medication Errors; Middle Aged; Monitoring, Physiologic; Thrombosis; Warfarin

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Analgesia, Obstetrical; Analgesics, Opioid; Anesthesiology; Anesthetics, General; Anticoagulants; Asthma; Drug-Related Side Effects and Adverse Reactions; Genetic Variation; Humans; Malignant Hyperthermia; Myocardial Infarction; Neuromuscular Depolarizing Agents; Pain, Postoperative; Perioperative Care; Pharmacogenetics; Practice Patterns, Physicians'; Succinylcholine; Warfarin

Protein C (PC) is a vitamin K-dependent proenzyme with anticoagulant activity, and patients with congenital PC deficiency are at high risk for thrombotic episodes. In patients with PC deficiency, starting treatment with oral anticoagulant drugs is associated with a transient hypercoagulable state and clinically overt thromboembolic complications before reaching a full anticoagulant effect. This report describes a successful supplementation with PC concentrate in two adult patients with moderately severe PC deficiency during the initiation of oral anticoagulation and a course of therapeutic dose of low-molecular-weight heparin for acute venous thromboembolism. Plasma PC levels above 50% were observed in both patients and maintained during the entire supplementation treatment period with PC concentrate until a stable therapeutic anticoagulation level has been reached. These results have been obtained within a short time, thus allowing a safe administration of a loading dose of warfarin. No adverse reactions to the PC concentrate, i.e. skin necrosis and other thromboembolic complications, bleedings or allergic reactions, were observed. We conclude that PC concentrate seems to be effective for the prevention of thromboembolic complications and safe in patients with congenital PC deficiency while initiating oral anticoagulants.

Topics: Adult; Anticoagulants; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Enoxaparin; Female; Heparin, Low-Molecular-Weight; Humans; International Normalized Ratio; Protein C; Protein C Deficiency; Treatment Outcome; Venous Thromboembolism; Warfarin

Topics: Drug Dosage Calculations; Drug Labeling; Drug-Related Side Effects and Adverse Reactions; Humans; Pharmacogenetics; Polymorphism, Genetic; Research Design; United States; United States Food and Drug Administration; Warfarin

Topics: Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Case-Control Studies; Confounding Factors, Epidemiologic; Drug-Related Side Effects and Adverse Reactions; Gastrointestinal Hemorrhage; Humans; Pharmacoepidemiology; Risk Factors; United Kingdom; Warfarin

We sought to examine the validity of specific hospital discharge codes in identifying drug toxicity precipitating hospitalization, among elderly users of high-risk medications.. We conducted a cross-sectional evaluation assessing the diagnostic test characteristics of International Classification of Diseases-9 External-Cause-of-Injury codes (E-codes) compared with a reference standard of medical record review. This study was nested within a prospective cohort of elders using warfarin, digoxin, or phenytoin as identified in the Pharmaceutical Assistance Contract for the Elderly benefit program.. We identified 4,803 subjects contributing 11,409 person-years of exposure to at least one of three drug groups. Subjects experienced 8,756 hospitalizations, of which 304 were deemed, by expert review, to be a result of an adverse event of warfarin, digoxin, or phenytoin. The sensitivity, specificity, and positive (PPVs) and negative predictive values for drug-specific E-codes were warfarin--25.5%, 98.3%, 46.6%, and 95.7%; digoxin--84.0%, 99.1%, 56.8%, and 99.8%; and phenytoin--86.7%, 98.7%, 59.1%, and 99.7%.. E-codes for digoxin and phenytoin have a high sensitivity, but E-codes for all three medications have poor PPVs, a result that might produce misclassification in studies based solely on discharge coding. Investigators should confirm such rare events via medical record review.

Topics: Adverse Drug Reaction Reporting Systems; Aged; Anti-Arrhythmia Agents; Anticoagulants; Anticonvulsants; Cross-Sectional Studies; Digoxin; Drug-Related Side Effects and Adverse Reactions; Forms and Records Control; Hospitalization; Humans; International Classification of Diseases; Medical Records; Patient Discharge; Pennsylvania; Phenytoin; Warfarin

Warfarin is the most widely used oral anticoagulant in the world for patients with venous thrombosis, pulmonary embolism, chronic atrial fibrillation, and prosthetic heart valves. Approximately 30 genes contribute to therapeutic effects of warfarin, and genetic polymorphisms in these genes may modulate its anticoagulant activity. In contrast to monogenic pharmacogenetic traits, warfarin drug response is a polygenic trait, and development of diagnostic tools predictive of adverse reactions to warfarin requires a novel approach. A combination of two strategies, biochemical isolation of allelic variants and linkage disequilibrium association studies, was used to find an association between genetic polymorphisms in the candidate genes and warfarin response. A strong association was found between genetic polymorphisms in six genes, including VKORC1, CYP2C9, PROC, EPHX1, GGCX, and ORM1, and interindividual variability in the anticoagulant effect of warfarin; the strongest predictors were VKORC1 and CYP2C9. Generation of single nucleotide polymorphism (SNP)-based dense genetic maps made it possible to identify haplotypes associated with drugresponse phenotypes. Discrimination between haplotypes associated with warfarin dose phenotypes can be achieved by a limited set of informative polymorphisms (tag SNPs). The use of tag SNPs in pharmacogenomic analysis provides a promising tool for dissecting polygenic traits of drug response.

Topics: Animals; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Carbon-Carbon Ligases; Cytochrome P-450 CYP2C9; Drug-Related Side Effects and Adverse Reactions; Epoxide Hydrolases; Genotype; Humans; Mixed Function Oxygenases; Orosomucoid; Pharmacogenetics; Polymorphism, Single Nucleotide; Protein C; Vitamin K Epoxide Reductases; Warfarin

In drug discovery today, drug exposure is determined in preclinical efficacy and safety studies and drug effects are related to measured concentrations rather than to the administered dose. This leads to a strong increase in the number of bioanalytical samples, demanding the development of higher throughput methods to cope with the increased workload. Here, a combined approach is described for the high-throughput preparation and liquid chromatography/tandem mass spectrometry (LC/MS/MS) analysis of drug levels in plasma samples from the preclinical efficacy and safety studies, i.e. exposure studies. Appropriate pharmacokinetic (PK) compartmental models were fitted to data from PK screening studies in the rat, which were subsequently used to simulate the expected plasma concentrations of the respective exposure studies. Information on the estimated drug concentrations was used to dilute the samples to appropriate concentration levels. A Tecan Genesis RSP liquid handling system was utilized to perform automated plasma sample preparation including serial dilution of standard solutions, dilution of plasma samples, addition of internal standard solution and precipitation with acetonitrile. This robotic sample preparation process permitted two studies of 1-96 samples each to be run simultaneously. To ensure the performance of this method the accuracy and precision for diazepam were examined. Two novel drugs were used to illustrate the suggested approach. In conclusion, our method for sample preparation of exposure samples, based on the combined use of PK simulations, a liquid handling system and a fast LC/MS/MS method, increased the throughput more than three times and minimized the errors, while maintaining the required accuracy and precision.

Topics: Animals; Anti-Anxiety Agents; Chromatography, Liquid; Computer Simulation; Diazepam; Drug Evaluation, Preclinical; Drug-Related Side Effects and Adverse Reactions; Male; Molecular Structure; Pharmaceutical Preparations; Rats; Rats, Sprague-Dawley; Reference Standards; Robotics; Tandem Mass Spectrometry; Time Factors; Warfarin

Topics: Anticoagulants; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Family Practice; Humans; Pharmacogenetics; Polymorphism, Genetic; United States; Warfarin

Topics: Aged; Anti-Arrhythmia Agents; Anticoagulants; Cross-Sectional Studies; Digoxin; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Emergency Service, Hospital; Humans; Hypoglycemic Agents; Insulin; Medical Errors; United States; Warfarin

The Beers criteria identify inappropriate use of medications in older adults. The number of and risk for adverse events from these medications are unknown.. To estimate the number of and risk for emergency department visits for adverse events involving Beers criteria medications compared with other medications.. Nationally representative, public health surveillance of adverse drug events and a cross-sectional survey of outpatient medical visits.. National Electronic Injury Surveillance System-Cooperative Adverse Drug Event Surveillance System, 2004-2005; National Ambulatory Medical Care Survey, 2004; and National Hospital Ambulatory Medical Care Survey, 2004.. Persons 65 years of age or older seeking emergency department and outpatient care.. Estimated number of and risks for emergency department visits for adverse drug events involving Beers criteria medications and other medications.. Among U.S. patients 65 years of age or older, an estimated 177,504 emergency department visits (95% CI, 100,155 to 254,854 visits) for adverse drug events occurred both years. An estimated 3.6% (CI, 2.8% to 4.5%) of these visits were for adverse events medications considered to be always potentially inappropriate, according to the Beers criteria, and 33.3% (CI, 27.8% to 38.7%) of visits were for adverse events from 3 other medications (warfarin [17.3%], insulin [13.0%], and digoxin [3.2%]). Accounting for outpatient prescription frequency, the risk for emergency department visits for adverse events due to these 3 medications was 35 times (CI, 9.6 to 61) greater than that for medications considered to be always potentially inappropriate.. Adverse events were identified only in emergency departments.. Compared with other medications, Beers criteria medications caused low numbers of and few risks for emergency department visits for adverse events. Performance measures and interventions targeting warfarin, insulin, and digoxin use could prevent more emergency department visits for adverse events.

Topics: Aged; Anti-Arrhythmia Agents; Anticoagulants; Cross-Sectional Studies; Digoxin; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Emergency Service, Hospital; Humans; Hypoglycemic Agents; Insulin; Medical Errors; United States; Warfarin

Adverse drug reactions (ADRs) account for 3.2-7% of acute hospital admissions. The aim of this study was to assess prospectively knowledge of ADRs in patients admitted through the emergency department of a teaching hospital.. Three hundred and ninety-nine patients were admitted on acute medical call during study periods in September 2002 and May 2003. One hundred gave their perception of the risk of ADRs using visual analogue scales, where 0 indicates minimum and 10 maximum risk. The medications studied were warfarin, proton pump inhibitors (PPIs), corticosteroids, nonsteroidal anti-inflammatory drugs (NSAIDs) and aspirin. Responses are compared against a medical control group.. Corticosteroids were ranked most dangerous by patients (median score, 25th-75th centiles: 5.4, 2.9-8.7). Medical staff ranked NSAIDs as highest risk (6.2, 4.0-7.5). Patients identified NSAIDs as low risk (2.1, 0.7-4.9), perceiving the risk of cardiac arrhythmias and disturbance in liver biochemistry to be equivalent to risk of upper gastrointestinal ulceration and bleeding. Risk of haemorrhage was ranked as the most common ADR for warfarin by patients (8.6, 3.3-9.5) and medical staff (8.8, 7.6-9.3).. Patients underrate the risk of ADRs of their medications. While there is a good level of knowledge of ADRs amongst warfarin and aspirin users, there is a clear lack of knowledge regarding the risk of upper GI bleeding in NSAID users. Increased education may reduce the incidence of ADRs but it is more likely that it will serve to meet increasing patient expectations.

Topics: Acute Disease; Adrenal Cortex Hormones; Aged; Anti-Inflammatory Agents, Non-Steroidal; Anticoagulants; Aspirin; Drug-Related Side Effects and Adverse Reactions; Emergency Service, Hospital; Female; Health Knowledge, Attitudes, Practice; Humans; Inpatients; Male; Middle Aged; Proton Pump Inhibitors; Risk Assessment; Warfarin

Topics: Anticoagulants; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Humans; Patient Education as Topic; Warfarin

The FDA's Spontaneous Reporting System (SRS) database contains over 1.5 million adverse drug reaction (ADR) reports for 8620 drugs/biologics that are listed for 1191 Coding Symbols for Thesaurus of Adverse Reaction (COSTAR) terms of adverse effects. We have linked the trade names of the drugs to 1861 generic names and retrieved molecular structures for each chemical to obtain a set of 1515 organic chemicals that are suitable for modeling with commercially available QSAR software packages. ADR report data for 631 of these compounds were extracted and pooled for the first five years that each drug was marketed. Patient exposure was estimated during this period using pharmaceutical shipping units obtained from IMS Health. Significant drug effects were identified using a Reporting Index (RI), where RI = (# ADR reports / # shipping units) x 1,000,000. MCASE/MC4PC software was used to identify the optimal conditions for defining a significant adverse effect finding. Results suggest that a significant effect in our database is characterized by > or = 4 ADR reports and > or = 20,000 shipping units during five years of marketing, and an RI > or = 4.0. Furthermore, for a test chemical to be evaluated as active it must contain a statistically significant molecular structural alert, called a decision alert, in two or more toxicologically related endpoints. We also report the use of a composite module, which pools observations from two or more toxicologically related COSTAR term endpoints to provide signal enhancement for detecting adverse effects.

Topics: Adverse Drug Reaction Reporting Systems; Artificial Intelligence; Computers; Databases, Factual; Drug Prescriptions; Drug-Related Side Effects and Adverse Reactions; Endpoint Determination; Models, Molecular; Quantitative Structure-Activity Relationship; Software; United States; United States Food and Drug Administration

Certain medications are designed "high alert' because they could cause serious harm if used incorrectly. Which are the high-alert meds and how can errors be averted?

Topics: Clinical Protocols; Drug-Related Side Effects and Adverse Reactions; Heparin; Humans; Insulin; Management Quality Circles; Medication Errors; Medication Systems, Hospital; Morphine; Pharmaceutical Preparations; Potassium Chloride; Reference Standards; Safety Management; Warfarin

Topics: Blood Coagulation Disorders; Drug-Related Side Effects and Adverse Reactions; Hematuria; Humans; Intracranial Hemorrhages; Male; Middle Aged; Rodenticides; Warfarin

To assess the perception of the teratogenic risk of common medication by professionals and lay people.. A visual-analogue scale was used to measure the perceived percentage of mothers who will deliver a child with a malformation, including those exposed to a list of drugs. Fifteen general practitioners, 10 gynaecologists, 106 pre-clinical students, 150 students in their clinical training, 81 pregnant women and 63 non-pregnant women were interviewed.. The perception of the teratogenic risk related to medication used in pregnancy was higher than the recognised risk in all groups, and for all drugs. The risk associated with safe medications was perceived to be higher by non-pregnant women as compared with the pregnant women. Pregnant women perceived the medication associated risk to be higher than physicians did for all drugs included in the questionnaire.. The high and unrealistic perception of teratogenic risk amongst women and health professionals may lead to abortions of otherwise wanted and healthy children.

Topics: Abnormalities, Drug-Induced; Chi-Square Distribution; Drug-Related Side Effects and Adverse Reactions; Erythromycin; Female; Health Knowledge, Attitudes, Practice; Humans; Physicians; Pregnancy; Risk Factors; Students, Medical; Teratogens; Warfarin

Topics: Aged; Analgesics, Opioid; Angiotensin-Converting Enzyme Inhibitors; Anticoagulants; Barbiturates; Chlorpropamide; Cholinergic Antagonists; Contraindications; Diuretics; Drug Prescriptions; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Frail Elderly; Health Services for the Aged; Humans; Hypoglycemic Agents; Kidney Function Tests; Meperidine; Monitoring, Physiologic; Patient Education as Topic; Quality Indicators, Health Care; Warfarin

The article describes Fairview Health System's participation in the Institute for Healthcare Improvement Breakthrough Series on adverse drug events and medication errors. Fairview commissioned an interdisciplinary team to design, plan, and lead activities focused on reducing adverse drug events and medication errors. This team managed, facilitated, or led 15 separate projects, each focusing on a specific aspect of the medications process. Specific systems improvements were identified, leading to reductions in errors or adverse events. As a result of this effort, Fairview has committed to a long-term plan to reduce the risk of adverse drug events and medication errors to the lowest possible rate.

Topics: Anticoagulants; Antineoplastic Agents; Delivery of Health Care, Integrated; Drug-Related Side Effects and Adverse Reactions; Electronic Data Processing; Forms and Records Control; Formularies as Topic; Humans; Hypnotics and Sedatives; Insulin; Medical Records; Medication Errors; Medication Systems; Minnesota; Renal Agents; Total Quality Management; Warfarin

Topics: Abnormalities, Drug-Induced; Acute Disease; Aged; Aged, 80 and over; Aging; Anticoagulants; Chronic Disease; Drug Hypersensitivity; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Forecasting; Gene Expression; Genetic Predisposition to Disease; Humans; Malignant Hyperthermia; Pharmacogenetics; Preventive Dentistry; Preventive Medicine; Risk; Treatment Outcome; 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: Anticoagulants; Cimetidine; Drug Information Services; Drug Prescriptions; Drug Utilization; Drug-Related Side Effects and Adverse Reactions; Humans; Hypnotics and Sedatives; Kinetics; Patient Care Planning; Patient Compliance; Pharmacology, Clinical; Thrombophlebitis; Warfarin

The Obstetric Drug Information Service at the Queen Victoria Medical Center in Melbourne, Australia aims to provide relevant information relating to drug use in pregnancy. A preliminary study conducted by the Center revealed that 62.5% of pregnant women consumed drugs during their pregnancies (excluding iron and vitamins), with an average of 3 drugs per woman. Certain drugs are relatively safer than others, and the selection of the appropriate drug for a pregnant patient is very important to the future health and well-being of the child. At least 5% of all birth defects are drug induced. The drugs that produce fetal abnormalities are called "dysmorphogens" or "teratogens". General principles of drug use in pregnancy are outlined. These include the following: 1) no drug should be considered 100% safe to the developing fetus, including topical preparations; 2) a true indication must be present for the administration of any drug; 3) the potential benefits should always be weighed against the possible hazards of that drug to the mother and the fetus; and 4) the effect of a drug on the fetus may not necessarily be the same as the intended pharmacological effect on the mother. The following specific drug induced embryopathies are reviewed: fetal alcohol syndrome; Warfarin syndrome; fetal hydantoin syndrome; stilbestrol (diethylstilbestrol, DES) syndrome, VACTERL syndrome, and thalidomide embryopathy. Drugs which are safe for use in pregnancy are analgesics, hypnosedatives, antibiotics, antiemetics and antihistamines, psychotherapeutic drugs, antihypertensive drugs, antituberculous drugs, antimalarial drugs, antithyroid drugs, and antidiabetic drugs.

Topics: Abnormalities, Drug-Induced; Abnormalities, Multiple; Analgesics; Anti-Bacterial Agents; Antiemetics; Antihypertensive Agents; Antimalarials; Antitubercular Agents; Diethylstilbestrol; Drug-Related Side Effects and Adverse Reactions; Female; Fetal Alcohol Spectrum Disorders; Fetus; Histamine H1 Antagonists; Humans; Hydantoins; Hypnotics and Sedatives; Hypoglycemic Agents; Infant, Newborn; Pregnancy; Pregnancy Complications; Psychotropic Drugs; Warfarin

This study was attempted to determine whether the native alcoholic drugs had any significant role in the pathogenesis of the APCD syndrome. The native alcoholic drugs, breast milk and maternal serum were analysed for vitamin K antagonists (dicoumarol, warfarin and coumarin). No vitamin K antagonists were detected from 14 commercial native alcoholic drugs, but one of the two homemade samples had a positive test of coumarin but not dicoumarol and warfarin. Seven breast milk and serum samples from the mothers of APCD infants showed no detectable amount of vitamin K antagonists. Negative results were found in 35 postpartum women who did not consume the drugs and 22 postpartum women who took the drugs. The results suggested that the native alcoholic drugs are unlikely to be the etiological factor of APCD syndrome.

Topics: Alcohols; Coumarins; Dicumarol; Drug-Related Side Effects and Adverse Reactions; Female; Humans; Hypoprothrombinemias; Infant; Infant, Newborn; Medicine, East Asian Traditional; Pregnancy; Warfarin

The data on adverse drug reactions (ADRs) are incomplete, unrepresentative, uncontrolled, and lacking in operational criteria for identifying ADRs. No quantitative conclusions can be drawn from the reported data in regard to morbidity, mortality, or the underlying causes of ADRs, and attempts to extrapolate the available data to the general population would be invalid and perhaps misleading. To evaluate the impact as well as the causes of ADRs, representative populations, including general hospital and ambulatory patients of all medical specialties, must be studied, and operationally defined criteria must be used to establish the presence of an ADR in a prospective study that incorporates appropriate control populations. Similar studies on the benefits of drug use are needed to provide perspective on the risk-benefit aspects of drug therapy. Until such studies are performed, estimates of the nature and scope of the ADR problem can be only guesses.

Topics: Anti-Bacterial Agents; Antihypertensive Agents; Aspirin; Costs and Cost Analysis; Digitalis Glycosides; Diuretics; Drug Interactions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Hospitalization; Pharmaceutical Preparations; Prospective Studies; Steroids; Tranquilizing Agents; United States; Warfarin

Topics: Adolescent; Adult; Age Factors; Aged; Drug Interactions; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Edema; Ethnicity; Female; Glyburide; Glycyrrhiza; Hematologic Diseases; Hospitalization; Humans; Male; Middle Aged; New Zealand; Outpatient Clinics, Hospital; Phenobarbital; Plants, Medicinal; Purpura, Thrombocytopenic; Quinidine; Sex Factors; Succinates; Triterpenes; Warfarin

These discussions are selected from the weekly staff conferences in the Department of Medicine, University of California Medical Center, San Francisco. Taken from transcriptions, they are prepared by Drs. Martin J. Cline and Hibbard E. Williams, Associate Professors of Medicine, under the direction of Dr. Lloyd H. Smith, Jr., Professor of Medicine and Chairman of the Department of Medicine.

Topics: Adult; Aged; Child, Preschool; Chromosome Aberrations; Chromosome Disorders; Congenital Abnormalities; Drug Hypersensitivity; Drug Tolerance; Drug-Related Side Effects and Adverse Reactions; Female; Genotype; Glucosephosphate Dehydrogenase Deficiency; Hemolysis; Humans; Isoniazid; Male; Pharmaceutical Preparations; Pharmacogenetics; Primaquine; Warfarin

Topics: Chlorpropamide; Digoxin; Drug-Related Side Effects and Adverse Reactions; Indomethacin; Penicillins; Prednisone; Streptomycin; Tetracycline; Thiopental; Warfarin

Topics: Aminocaproates; Animals; Blood Coagulation Disorders; Blood Transfusion; Drug-Related Side Effects and Adverse Reactions; Fibrinogen; Fibrinolysis; Fibrinolytic Agents; Hemorrhage; Heparin; Humans; Rats; Streptokinase; Thrombosis; Warfarin

Topics: Adrenal Cortex Hormones; Anti-Bacterial Agents; Anticoagulants; Digitalis Glycosides; Drug Hypersensitivity; Drug Therapy; Drug-Related Side Effects and Adverse Reactions; Epidemiology; Hospitals; Humans; Medical Records; Methicillin; Toxicology; Warfarin