warfarin and Substance-Related-Disorders

Delta-9-tetrahydrocannabinol (THC), the main psychoactive cannabinoid in cannabis, may inhibit the cytochrome P450 enzyme CYP2C9. Consequently, cannabis use might infer a risk of drug-drug interaction with substrates for this enzyme, which includes drugs known to have a narrow therapeutic window. In this study, we describe a case report of a 27-year-old man treated with warfarin due to mechanical heart valve replacement who presented with elevated international normalized ratio (INR) value (INR = 4.6) following recreational cannabis use. We conducted a review of the available literature, using the PubMed and EMBASE databases while following PRISMA guidelines. Following screening of 85 articles, three eligible articles were identified, including one in vitro study and two case reports. The in vitro study indicated that THC inhibits the CYP2C9-mediated metabolism of warfarin. One case study reported of a man who on two occasions of increased marijuana use experienced INR values above 10 as well as bleeding. The other case study reported of a patient who initiated treatment with a liquid formulation of cannabidiol for the management of epilepsy, ultimately necessitating a 30% reduction in warfarin dose to maintain therapeutic INR values. The available, although sparse, data suggest that use of cannabinoids increases INR values in patients receiving warfarin. Until further data are available, we suggest patients receiving warfarin be warned against cannabis use.

Topics: Adult; Anticoagulants; Cannabis; Cytochrome P-450 CYP2C9; Cytochrome P-450 CYP2C9 Inhibitors; Dronabinol; Drug Interactions; Endocarditis; Heart Valve Prosthesis Implantation; Humans; International Normalized Ratio; Male; Marijuana Smoking; Stroke; Substance-Related Disorders; Warfarin

Oral vitamin K antagonists are highly efficacious in the prevention and treatment of thromboembolic disease. Optimal use of these agents in clinical practice is challenged by their narrow therapeutic window. The proportion of time spent in the International Normalized Ratio (INR) range of 2.0-3.0 [time in the therapeutic range (TTR)] has been closely associated with adverse outcomes, i.e., stroke, hemorrhage, mortality. Although TTR is a validated marker, it has several limitations. TTR does not capture short-term risks associated with highly variable periods or periods characterized by extreme deviations in INR. Because TTR measurement is limited to consecutive periods of warfarin exposure, it does not inform the risks associated with gap periods of 56 days or greater as these time intervals are excluded from end-point rate calculations. Because individuals with gaps in monitoring represent a different patient population than those without gaps, e.g., less adherent, more acutely ill, more frequent transitions in health status, TTR analyses are likely most valid and informative for individuals with uninterrupted monitoring of the INR. Duration of warfarin therapy and patient-specific factors have also been shown to influence TTR. Younger age, female sex, lower income, black race, frequent hospitalizations, polypharmacy, active cancer, decompensated heart failure, substance abuse, psychiatric disorders, dementia, and chronic liver disease have all been associated with lower TTR. Targeted strategies to improve TTR are urgently needed.

Topics: Age Factors; Anticoagulants; Chronic Disease; Female; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Liver Diseases; Male; Neoplasms; Sex Factors; Stroke; Substance-Related Disorders; Thromboembolism; Vitamin K; Warfarin

Limb abnormalities are one of the most common and visible phenotypic effects of several human teratogens. The specific effects are different for most teratogens and include effects on limb morphogenesis (thalidomide, warfarin, phenytoin, valproic acid) and the effect of vascular disruption on a limb that had formed normally (misoprostol, chorionic villus sampling, and phenytoin). Either duplication (preaxial polydactyly of hands and feet) or deficiency (absence of thumb) is a common effect of thalidomide; no other human teratogen identified to date has this effect on the developing limb. Procedures during pregnancy, including chorionic villus sampling and dilation and curettage, produce defects of vascular disruption. For common exposures, such as alcohol and cocaine, it has been difficult to confirm objectively the exposure during embryogenesis and to ascribe specific limb defects that are produced. The molecular basis for the limb defects produced by the recognized human teratogens remains unknown.

Topics: Chorionic Villi Sampling; Female; Humans; Limb Deformities, Congenital; Male; Misoprostol; Phenytoin; Pregnancy; Pregnancy in Diabetics; Substance-Related Disorders; Teratogens; Thalidomide; Valproic Acid; Warfarin

Synthetic cannabinoids are swiftly gaining popularity and have earned a reputation of being relatively safer than other illicit drugs. However, there is a growing body of literature associating thromboembolic events with their use.. A 32-year-old woman presented on four separate occasions with a new thromboemoblic event after smoking synthetic cannabinoids. She had no medical history, and over the span of 9 months she developed two kidney infarcts, pulmonary emboli, and an ischemic stroke. Each of these events occurred within 24 hours of smoking synthetic cannabinoids. During periods of abstinence, she remained free of thrombotic events. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: This report shows that an association between thrombosis and the use of synthetic cannabinoids is reproducible and involves both venous and arterial thrombosis, suggesting activation of coagulation or inflammatory pathways. As the popularity of this drug continues to grow, we can expect to see a growing number of these cases. Synthetic cannabinoid use should be included in the differential diagnosis of young patients with no risk factors who present with venous or arterial thrombosis.

Topics: Adult; Anticoagulants; Aspirin; Cannabinoids; Enoxaparin; Female; Humans; Infarction; Platelet Aggregation Inhibitors; Pregnancy; Pulmonary Embolism; Risk Factors; Stroke; Substance-Related Disorders; Thromboembolism; Tomography, X-Ray Computed; Warfarin

While a considerable amount is known about which patient-level factors predict poor anticoagulation control with warfarin, measured by percent time in therapeutic range (TTR), less is known about predictors of time above or below target.. To identify predictors of different patterns of international normalized ratio (INR) values that account for poor control, including 'erratic' patterns, where more time is spent both above and below INR target, and unidirectional patterns, where time out of range is predominantly in one direction (low or high).. We studied 103 897 patients receiving warfarin with a target INR of 2-3 from 100 Veterans Health Administration sites between October 2006 and September 2008. Our outcomes were percent time above and below the target range. Predictors included patients' demographics, comorbidities, and other clinical data.. Predictors of erratic patterns included alcohol abuse (5.2% more time below and 3.7% more time above, P < 0.001 for all results), taking > 16 medications (4.6% more time below and 1.8% more time above compared to taking seven or fewer medications), and four or more hospitalizations during the study (6.6% more time below and 2% more time above compared to no hospitalization). In contrast, predictors like cancer, non-alcohol drug abuse, dementia, and bipolar disorder were associated with more time below the target range (3.4%, 5.2%, 2.6%, and 3.2%, respectively) and less (or similar) time above range.. Different patient-level factors predicted unidirectional below-target and 'erratic' patterns of INR control. Distinct interventions are necessary to address these two separate pathways to poor anticoagulation.

Topics: Adult; Aged; Alcoholism; Anticoagulants; Atrial Fibrillation; Bipolar Disorder; Blood Coagulation; Dementia; Female; Hospitalization; Humans; International Normalized Ratio; Male; Middle Aged; Multivariate Analysis; Neoplasms; Substance-Related Disorders; Time Factors; Treatment Outcome; United States; United States Department of Veterans Affairs; Venous Thromboembolism; Warfarin; Young Adult

The choice to recommend antithrombotic therapy to patients with atrial fibrillation should rely on cardioembolic and bleeding risk stratification. Sharing some risk factors, schemes to predict thrombotic and bleeding risk are expected not to be independent, yet the degree of their association has never been clearly quantified.. We described the cardioembolic (Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack [CHADS2]/Congestive heart failure, Hypertension, Age >75, Diabetes mellitus, and prior Stroke or transient ischemic attack, Vascular disease, Age 65-75, Sex category i.e. females [CHA2DS2-VASc]) and bleeding risk (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly [HAS-BLED]) co-distribution among patients of the Euro Heart Survey on atrial fibrillation. We measured the within-patient correlation (Spearman) and concordance between the 2 types of score and score-based risk categorization (low, intermediate, high). The score-based predicted risk co-classification was then related to the observed 1-year stroke and bleeding occurrence.. In 3920 patients, we found a between-scores correlation of 0.416 (P < .001) between HAS-BLED and CHADS2, and 0.512 (P < .001) between HAS-BLED and CHA2DS2-VASc. In 89% (CHADS2/HAS-BLED) and 97% (CHA2DS2-VASc/HAS-BLED) of patients, the bleeding risk category was equal to or lower than their cardioembolic risk category (P < .001 for symmetry test). A complete concordance between risk categories was found in 39.6% (CHADS2/HAS-BLED) and 21.7% (CHA2DS2-VASc/HAS-BLED) of patients; 4.4% (CHADS2/HAS-BLED) and 7.7% (CHA2DS2-VASc/HAS-BLED) of patients had high cardioembolic risk/low bleeding risk or vice versa. A tendency for an increasing frequency of stroke was observed for increasing bleeding risk within cardioembolic risk categories and vice versa.. In a real-world population with atrial fibrillation, we confirmed that the cardioembolic and bleeding risk classifications are correlated but not exchangeable. It is then worth verifying the advantages of a strategy adopting a combined risk assessment over a strategy relying only on the cardioembolic risk evaluation.

Topics: Age Distribution; Aged; Alcohol Drinking; Anticoagulants; Aspirin; Atrial Fibrillation; Diabetes Complications; Europe; Female; Health Surveys; Heart Failure; Hemorrhage; Humans; International Normalized Ratio; Male; Middle Aged; Risk Assessment; Sex Distribution; Stroke; Substance-Related Disorders; Thromboembolism; Warfarin

Warfarin is effective in preventing thromboembolic events, but concerns exist regarding its use in patients with substance abuse.. Identify which patients with substance abuse who receive warfarin are at risk for poor outcomes.. Retrospective cohort study. Diagnostic codes, lab values, and other factors were examined to identify risk of adverse outcomes.. Veterans AffaiRs Study to Improve Anticoagulation (VARIA) database of 103,897 patients receiving warfarin across 100 sites.. Outcomes included percent time in therapeutic range (TTR), a measure of anticoagulation control, and major hemorrhagic events by ICD-9 codes.. Nonusers had a higher mean TTR (62 %) than those abusing alcohol (53 %), drugs (50 %), or both (44 %, p < 0.001). Among alcohol abusers, an increasing ratio of the serum hepatic transaminases aspartate aminotransferase/alanine aminotransferase (AST:ALT) correlated with inferior anticoagulation control; normal AST:ALT ≤ 1.5 predicted relatively modest decline in TTR (54 %, p < 0.001), while elevated ratios (AST:ALT 1.50-2.0 and > 2.0) predicted progressively poorer anticoagulation control (49 % and 44 %, p < 0.001 compared to nonusers). Age-adjusted hazard ratio for major hemorrhage was 1.93 in drug and 1.37 in alcohol abuse (p < 0.001 compared to nonusers), and remained significant after also controlling for anticoagulation control and other bleeding risk factors (1.69 p < 0.001 and 1.22 p = 0.003). Among alcohol abusers, elevated AST:ALT >2.0 corresponded to more than three times the hemorrhages (HR 3.02, p < 0.001 compared to nonusers), while a normal ratio AST:ALT ≤ 1.5 predicted a rate similar to nonusers (HR 1.19, p < 0.05).. Anticoagulation control is particularly poor in patients with substance abuse. Major hemorrhages are more common in both alcohol and drug users. Among alcohol abusers, the ratio of AST/ALT holds promise for identifying those at highest risk for adverse events.

Topics: Aged; Alcoholism; Anticoagulants; Comorbidity; Databases, Factual; Drug Administration Schedule; Female; Hemorrhage; Humans; Male; Middle Aged; Retrospective Studies; Risk Factors; Substance-Related Disorders; United States; Veterans; Veterans Health; Warfarin

Topics: Anticoagulants; Female; Humans; Male; Substance-Related Disorders; Warfarin

Warfarin pharmacogenomic algorithms reduce dosing error, but perform poorly in non-European-Americans. Electronic health record (EHR) systems linked to biobanks may allow for pharmacogenomic analysis, but they have not yet been used for this purpose.. We used BioVU, the Vanderbilt EHR-linked DNA repository, to identify European-Americans (n = 1022) and African-Americans (n = 145) on stable warfarin therapy and evaluated the effect of 15 pharmacogenetic variants on stable warfarin dose.. Associations between variants in VKORC1, CYP2C9 and CYP4F2 with weekly dose were observed in European-Americans as well as additional variants in CYP2C9 and CALU in African-Americans. Compared with traditional 5 mg/day dosing, implementing the US FDA recommendations or the International Warfarin Pharmacogenomics Consortium (IWPC) algorithm reduced error in weekly dose in European-Americans (13.5-12.4 and 9.5 mg/week, respectively) but less so in African-Americans (15.2-15.0 and 13.8 mg/week, respectively). By further incorporating associated variants specific for European-Americans and African-Americans in an expanded algorithm, dose-prediction error reduced to 9.1 mg/week (95% CI: 8.4-9.6) in European-Americans and 12.4 mg/week (95% CI: 10.0-13.2) in African-Americans. The expanded algorithm explained 41 and 53% of dose variation in African-Americans and European-Americans, respectively, compared with 29 and 50%, respectively, for the IWPC algorithm. Implementing these predictions via dispensable pill regimens similarly reduced dosing error.. These results validate EHR-linked DNA biorepositories as real-world resources for pharmacogenomic validation and discovery.

Topics: Adult; Aged; Aged, 80 and over; Anticoagulants; Aryl Hydrocarbon Hydroxylases; Black or African American; Calcium-Binding Proteins; Cytochrome P-450 CYP2C9; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 4; Dose-Response Relationship, Drug; Drug Administration Schedule; Electronic Health Records; Female; Humans; Male; Middle Aged; Mixed Function Oxygenases; Polymorphism, Single Nucleotide; Substance-Related Disorders; Vitamin K Epoxide Reductases; Warfarin; White People

Our goal was to establish whether psychosocial risk factors for nonadherence, previously identified as negative predictors of warfarin prescribing, are predictors of adverse events for patients with nonvalvular atrial fibrillation receiving warfarin.. Retrospective cohort analysis.. Ohio Medicaid administrative database.. We studied Ohio Medicaid recipients with nonvalvular atrial fibrillation receiving warfarin to determine whether a history of substance abuse, psychiatric illness, or social factors (identified as conditions perceived to be barriers to adherence) are predictors of adverse events, including stroke, intracranial hemorrhage, and gastrointestinal bleeding. Multivariable risk ratios were calculated for each risk factor using Cox proportional hazards models.. 9,345 patients were identified as having nonvalvular atrial fibrillation and receiving 2 or more warfarin prescriptions between 1997 and 2002. The event rates for the sample as a whole were 1.5 strokes, 0.7 intracranial hemorrhages, and 4.3 gastrointestinal bleeds per 100 person-years of follow-up. Subjects with substance abuse had the highest adjusted risk ratio, 2.4 (95% confidence interval [CI]: 1.4, 4.0) for an intracranial hemorrhage while receiving warfarin, followed by subjects with psychiatric illness, adjusted risk ratio of 1.5 (95% CI: 1.04, 2.1). Subjects with psychiatric illness also had an adjusted risk ratio of 1.4 (95% CI: 1.1, 1.7) for stroke. Patients in all 3 identified risk groups were at a significantly increased risk of gastrointestinal bleeding.. Patients with nonvalvular atrial fibrillation treated with warfarin who have psychosocial risk factors for nonadherence have an increased risk of adverse events.

Topics: Aged; Aged, 80 and over; Anticoagulants; Atrial Fibrillation; Cohort Studies; Female; Gastrointestinal Hemorrhage; Humans; Intracranial Hemorrhages; Male; Mental Disorders; Middle Aged; Retrospective Studies; Risk Factors; Socioeconomic Factors; Stroke; Substance-Related Disorders; Treatment Outcome; Treatment Refusal; Warfarin

The effects of implementing a warfarin-monitoring service for inpatients were evaluated. The pharmacy-managed service includes chart review, laboratory interpretation, recommendations for warfarin dosage adjustments, physician and patient education, and coordination of follow-up in the outpatient anticoagulation clinic. In a before-after trial, 52 patients monitored by the warfarin-monitoring service were compared with 97 patients who received warfarin before the service was implemented. Significantly fewer determinations of prothrombin time (PT) and partial thromboplastin time (PTT) were ordered for after-trial patients compared with before-trial patients. PT stability at hospital discharge was significantly improved in after-trial patients. After-trial patients were 12.2 times more likely to be referred to the anticoagulation clinic. No difference was found between the before and after groups in overall compliance with follow-up; however, among patients with no history of substance abuse, after-trial patients were 6.7 times more likely to be compliant. The warfarin-monitoring service had no significant effect on the number of hospital visits and readmissions related to toxicity and recurrence of thrombosis. After-trial patients were 5.4 times more likely to have a therapeutic PT at the initial follow-up appointment. The warfarin-monitoring service improved warfarin dose determination, improved PT stability, and increased referrals to the anticoagulation clinic; among patients with no history of substance abuse, it also improved clinic compliance.

Topics: Drug Monitoring; Evaluation Studies as Topic; Female; Humans; Inpatients; Male; Middle Aged; Outpatient Clinics, Hospital; Outpatients; Patient Compliance; Patient Education as Topic; Pharmacists; Pharmacy Service, Hospital; Prothrombin Time; Recurrence; Substance-Related Disorders; Warfarin

Because of the emergence of warfarin resistance, new potent long-acting anticoagulants are now readily available in several over-the-counter rodenticide products. The availability of these "superwarfarin" compounds has led to accidental and purposeful human ingestions, one of which has resulted in a death. We summarize the prior case reports and report a second death. In addition, we report the availability of an assay to detect the presence of brodifacoum (a superwarfarin compound) in human plasma and tissues.

Topics: 4-Hydroxycoumarins; Adult; Female; Humans; Kidney; Liver; Osmolar Concentration; Rodenticides; Substance-Related Disorders; Vitamin K; Warfarin

Topics: Adult; Female; Humans; Menorrhagia; Substance-Related Disorders; Warfarin

A case of surreptitious ingestion of oral anticoagulants is presented. The patient, a 31-year-old nurse, was followed for more than 3 years and underwent thorough psychological and psychiatric evaluation. Anticoagulant malingerers are by no means rare; however, little is known about the psychiatric disturbances in these patients. The tendency has been to regard these patients as having neurotic or personality disturbances. The data in the present case suggest that factitious hemorrhagic disease is caused by a psychotic disturbance. The results of psychiatric therapy are discussed.

Topics: Adult; Denial, Psychological; Diagnosis, Differential; Female; Haloperidol; Hemorrhage; Humans; Psychological Tests; Psychotherapy, Group; Psychotic Disorders; Substance-Related Disorders; Warfarin

The authors present the case of a 61-year-old woman who became increasingly sensitive to her warfarin. When she remained anticoagulated during a 2-month period off of warfarin a plasma analysis detected warfarin indicating she was taking the anticoagulant surreptitiously. This patient demonstrated features of factitious illness including a background of unsatisfactory childhood relationships, average intelligence, a lack of psychosis, and no obvious secondary gain. Surreptitious use of anticoagulants should be considered in all cases of unexplained hemorrhagic symptoms with low prothrombin activity.

Topics: Denial, Psychological; Drug Hypersensitivity; Female; Hemorrhage; Humans; Middle Aged; Prothrombin Time; Substance-Related Disorders; Warfarin

Topics: Adult; Hematuria; Humans; Male; Substance-Related Disorders; Warfarin

A young woman presented with a 2 year history of a severe bleeding disorder and marked deficiencies in all four vitamin-K-dependent factors. Metabolic studies with tracer doses of tritium-labelled vitamin K1 suggested that the patient might be taking an oral anticoagulant; and subsequently her plasma was found to contain a substance identical to phenindione in its spectrophotometric and chromatographic properties. The half-disappearance times of factors II, IX, X were measured after the administration of a concentrate of these factors and were found to conform with published figures. The concentrate controlled the patient's excessive bruising and prolonged skin and gingival bleeding. It would therefore seem that factor VII may not be essential in reversal of the bleeding disorder induced by anticoagulant overdose.

Topics: Adult; Anemia; Blood Coagulation Disorders; Blood Coagulation Factors; Blood Coagulation Tests; Chromatography, Gas; Chromatography, Thin Layer; Diabetes Complications; Female; Glucosephosphate Dehydrogenase; Hematemesis; Hematuria; Humans; Menorrhagia; Phenindione; Self Medication; Spectrum Analysis; Substance-Related Disorders; Vitamin K; Warfarin