Should We Reintroduce Previous Venous Thromboembolism Into Decision-Making for Anticoagulation in Atrial Fibrillation?

BackgroundWe aimed to investigate whether history of venous thromboembolism should be considered a prognostic factor for future thromboembolic events in patients with atrial fibrillation.MethodsThis was a nationwide cohort study of patients with incident atrial fibrillation from 2000-2017, defined and characterized using Danish health registries. Cox regression analyses were used to calculate hazard ratios and 95% confidence intervals for the outcomes ischemic stroke or systemic embolism, and ischemic stroke, systemic embolism, or venous thromboembolism, according to history of venous thromboembolism. Analyses were adjusted for components of the CHA₂DS₂-VASc score and time-varying use of oral anticoagulation.ResultsThe study included 246,313 patients with incident atrial fibrillation, of which 6,516 (2.6%) had previous venous thromboembolism. Patients with previous venous thromboembolism carried an overall similar adjusted risk of ischemic stroke or systemic embolism compared with patients without previous venous thromboembolism (reference; hazard ratio 0.99; 95% confidence interval, 0.90-1.09). When analyzing a composite thromboembolic outcome of ischemic stroke, systemic embolism, or venous thromboembolism, patients with previous venous thromboembolism were at high-risk (hazard ratio 1.76; 95% confidence interval, 1.64-1.90). Similar conclusions were drawn when stratifying by venous thromboembolism subtype, and when restricting to patients with low CHA₂DS₂-VASc scores or the non-anticoagulated subset of the study population.ConclusionPatients with atrial fibrillation and previous venous thromboembolism carried similar risk of ischemic stroke or systemic embolism compared with patients with atrial fibrillation without previous venous thromboembolism. Nonetheless, patients with previous venous thromboembolism remain a high-risk population due to an excess risk of future venous thromboembolism. Patients and physicians should keep this excess thromboembolic risk in mind when weighing the expected risks and benefits of oral anticoagulation in patients with atrial fibrillation.     

High Fluctuation Between Anticoagulants,Frequent Off-Label Dosing,and No Difference Concerning Outcomes: Results of a Real-Life Cohort Study

BackgroundRecently published studies indicated a high proportion of patients taking direct oral anticoagulants (DOACs) are off-label under- or overdosed. The present study aimed at investigating whether off-label dosages are corrected over time and whether off-label doses are associated with differences in bleeding rates, ischemic stroke, or venous thromboembolism.MethodsIn this retrospective cohort study, patients presenting to our emergency department between January 1 and December 31, 2018, with therapeutic oral anticoagulation were included (ie, vitamin-K antagonists [VKAs], rivaroxaban, apixaban, edoxaban, and dabigatran) and follow-up for a maximum of 2 years until December 31, 2019, was made. Detailed chart reviews were performed for each case concerning characteristics, indication, bleeding complications, or changes in the used substance or dosage.ResultsWe reviewed 2588 consultations of 1228 patients receiving therapeutic oral anticoagulation. During the maximum follow-up period of 2 years vitamin K antagonists and rivaroxaban lost the largest proportions in favor of apixaban. The overall distribution of dosage correctness remained almost unimproved (correct dosing in 62.5%, underdosing in 23.6%, coverdosing in 13.9%).The corresponding outcomes did not differ with respect to bleeding events, ischemic stroke, or venous thromboembolism among various anticoagulants as well as between correct and off-label doses.ConclusionsA rising proportion of existing oral anticoagulation regimes was changed to apixaban, while the proportion of off-label dosages of all oral anticoagulants remained stable. No difference in bleeding rates, de novo strokes, or thromboembolisms was found between anticoagulants as well as between correct and off-label doses.     

A Contemporary 20-Year Cleveland Clinic Experience of Nonbacterial Thrombotic Endocarditis: Etiology,Echocardiographic Imaging,Management, and Outcomes

BackgroundNonbacterial thrombotic endocarditis, or marantic endocarditis, is rare. Contemporary data on the etiology, echocardiographic evaluation, and management of nonbacterial thrombotic endocarditis are limited.MethodsA single-center retrospective cohort study was performed. Electronic medical records and echocardiographic records were searched for patients ages ≥18 years with a confirmed diagnosis of nonbacterial thrombotic endocarditis between January 1999 and November 2019. Demographic, echocardiographic, and management data were collected.ResultsOf 600,577 transthoracic echocardiograms (TTEs) and 89,264 transesophageal echocardiograms (TEEs), 42 patients had nonbacterial thrombotic endocarditis (mean age: 54 ± 14.5 years; 66.7% were female). The median duration of follow-up was 8.2 (interquartile range 3.3-24.4) months. Seventeen patients (40.5%) had malignancy, 33.3% had systemic lupus erythematosus, and 35.7% had antiphospholipid antibody syndrome. Stroke was the most common presentation (59.5%).TTE enabled the diagnosis in 19 cases (45.2%), compared with TEE, which identified the condition in 33 of 34 (97.1%) cases in which it was utilized. Three-dimensional echocardiography was performed in 17 TEEs. The most common valves involved were mitral (61.9%), and aortic (23.8%) valves. Thirty-two patients were managed with anticoagulation. Ten patients underwent surgery. Sixteen (38.1%) patients died, most of whom had a diagnosis of advanced malignancy.ConclusionIn a contemporary 20-year cohort, TTE and TEE played important roles in diagnosis, with superior diagnostic performance of TEE for nonbacterial thrombotic endocarditis. Mortality was high, and advanced malignancy portended a worse prognosis. Management in most cases was therapeutic anticoagulation. In select cases, surgery provided favorable outcomes.     

Clinical Outcomes in Asymptomatic and Symptomatic Atrial Fibrillation Presentations in GARFIELD-AF: Implications for AF Screening

BackgroundAsymptomatic atrial fibrillation is often detected incidentally. Prognosis and optimal therapy for asymptomatic compared with symptomatic atrial fibrillation is uncertain. This study compares clinical characteristics, treatment, and 2-year outcomes of asymptomatic and symptomatic atrial fibrillation presentations.MethodsGlobal Anticoagulant Registry in the Field-Atrial Fibrillation (GARFIELD-AF) is a global, prospective, observational study of newly diagnosed atrial fibrillation with ≥1 stroke risk factors (http://www.clinicaltrials.gov, unique identifier: NCT01090362). Patients were characterized by atrial fibrillation-related symptoms at presentation and the CHA₂DS₂-VASc score. Two-year follow-up recorded anticoagulation patterns (vitamin K antagonist, direct oral anticoagulants, parenteral therapy) and outcomes (stroke/systemic embolism, all-cause mortality, and bleeding).ResultsAt presentation, of 52,032 eligible patients, 25.4% were asymptomatic and 74.6% symptomatic. Asymptomatic patients were slightly older (72 vs 70 years), more often male (64.2% vs 52.9%), and more frequently initiated on anticoagulation ± antiplatelets (69.4% vs 66.0%). No difference in events (adjusted hazard ratios, 95% confidence interval) for nonhemorrhagic stroke/systemic embolism (1.19, 0.97-1.45), all-cause mortality (1.06, 0.94-1.20), or bleeding (1.02, 0.87-1.19) was observed. Anticoagulation was associated with comparable reduction in nonhemorrhagic stroke/systemic embolism (0.59, 0.43–0.82 vs 0.78, 0.65–0.93) and all-cause mortality (0.69, 0.59-0.81 vs 0.77, 0.71-0.85) in asymptomatic versus symptomatic, respectively.ConclusionsMajor outcomes do not differ between asymptomatic and symptomatic atrial fibrillation presentations and are comparably reduced by anticoagulation. Opportunistic screening-detected asymptomatic atrial fibrillation likely has the same prognosis as asymptomatic atrial fibrillation at presentation and likely responds similarly to anticoagulation thromboprophylaxis.     

Pharmacogenetics of warfarin: regulatory, scientific, and clinical issues

Using pharmacogenetics-based therapy, clinicians can estimate the therapeutic warfarin dose by genotyping patients for single nucleotide polymorphisms (SNPs) that affect warfarin metabolism or sensitivity. SNPs in the cytochrome P450 complex (CYP2C9) affect warfarin metabolism: patients who have the CYP2C9*2 and/or CYP2C9*3 variants metabolize warfarin slowly and are more likely to have an elevated International Normalized Ratio INR or to hemorrhage during warfarin initiation than patients without these variants. SNPs in vitamin K epoxide reductase (VKORC1) correlate with warfarin sensitivity. Patients who are homozygous for a common VKORC1 promoter polymorphism, −1639 G>A (also designated as VKOR 3673, haplotype A, or haplotype*2), are warfarin sensitive and typically require lower warfarin doses. By providing an estimate of the therapeutic warfarin dose, pharmacogenetics-based therapy may improve the safety of anticoagulant therapy. To improve drug safety, the FDA updates labels of previously approved drugs as new clinical and genetic evidence accrues. The labels of medical products serve to inform prescribers and patients about potential ways to improve the benefit/risk ratio and/or optimize doses of medical products. On August 16, 2007, the FDA updated the label of warfarin to include information on pharmacogenetic testing and to encourage, but not require, the use of this information in dosing individual patients initiating warfarin therapy. The FDA completed the label update in August 2007. Disclosure: A portion of this article was adapted from an education handout that Dr. Gage has retained copyright of: Gage, B.F. (2006). Pharmacogenetics-based coumarin therapy. Hematology Am Soc Hematol Educ Program: 467–473. Dr. Gage has served as a consultant to Bristol-Myers Squibb. Funding: NIH R01 HL074724.     

Long-term citrate anticoagulation in chronic hemodialysis patients

In some cases, long-term (>3 months) citrate anticoagulation is needed in maintenance hemodialysis patients due to a persistent bleeding risk. In this retrospective observational study, we present our experience and assess its safety and effects on mineral and bone disorder parameters. Sixteen patients (mean age 67 ± 15 years) were treated with long-term citrate anticoagulation. The indications were: recurrent gastrointestinal bleeding in nine patients, heparin-induced thrombocytopenia, retroperitoneal hematoma, chronic subdural hematoma, proliferative diabetic retinopathy, vascular malformations in the brain in one patient, and others in two patients. Metabolic complications and intact parathyroid hormone (iPTH) were analyzed. Citrate anticoagulation was performed for 4 months to 6.3 years (median 12 months). Ionized calcium was stable during the procedures; hypocalcemia (<0.9 mmol/L) was rare (2.1% of procedures), and there was one case of severe symptomatic hypocalcemia. There were no clinically significant acid-base disturbances and no clotting problems. In the short term (1-3 months after starting citrate), the iPTH increased in 73% of patients (from 325 ± 310 to 591 ± 793 pg/L, P = 0.11, N = 11). In the long term (1-2 years), an increase in iPTH was observed in 3/6 patients. The time period (before/after starting citrate) was a significant predictor of iPTH using main-effects anova (P < 0.001). To conclude, long-term citrate anticoagulation in chronic hemodialysis patients is safe. Mild hypocalcemia during dialysis with citrate anticoagulation may contribute to a short- and long-term increase in iPTH in these patients. Further studies on long-term citrate anticoagulation are necessary.     

Prevalence of oral anticoagulation in atrial fibrillation

OBJECTIVES:

Atrial fibrillation is the most common sustained arrhythmia and is associated with poor outcomes, including stroke. The ability of anticoagulation therapy to reduce the risk of stroke has been well established; however, the prevalence of anticoagulation therapy use in the Public Health System is unknown. The aim of this study is to evaluate both the prevalence of anticoagulation therapy among patients with atrial fibrillation and the indications for the treatment.

METHODS:

In this cross-sectional study, we included consecutive patients who had atrial fibrillation documented by an electrocardiogram performed between September 2011 and March 2012 at a university hospital of the Public Health System. The variables analyzed included the risk of a thromboembolic event and/or bleeding, the use of antiplatelet or anticoagulation therapy, the location where the electrocardiogram report was initially reviewed and the specialty of the physician who initially reviewed it.

RESULTS:

We included 162 patients (mean age 68.9 years, 56% men). Hypertension (90.1%), heart failure (53.4%) and stroke (38.9%) were the most prevalent diseases found. Only 50.6% of the patients knew that they had atrial fibrillation. Regarding the use of therapy, only 37.6% of patients classified as high risk according to the CHADS2 scores and 35.5% according to the CHA2DS2VASc used oral anticoagulation. A presumptive diagnosis of heart failure and the fact that the electrocardiogram was evaluated by a cardiologist were the only independent predictors of the use of anticoagulants.

CONCLUSIONS:

Our study found a low prevalence of oral anticoagulation therapy among patients with atrial fibrillation and an indication for stroke prophylaxis for the use of this therapy, including among those with high CHADS2 and CHA2DS2VASc scores.     

Recurrent venous thromboembolism while on anticoagulant therapy

There has been immense progress in the management of venous thromboembolism in recent years with increased awareness and adequate thromboprophylaxis proving successful in reducing the morbidity and mortality associated with this condition. One of the commonest complications of an initial venous thrombosis is the development of recurrent thrombosis. Unlike in the case of the first clot, the diagnosis and management of the recurrent episode remain a difficult issue. Even more challenging is the clinical situation where a new thrombus develops while the patient is being treated with anticoagulant medication for a previous clot. The clinical approach and management of these patients are complex, and require understanding of the differences in thrombus development in the different clinical circumstances.     

Electrochemical Assay of Heparin to Monitor Anticoagulation Action in Cardiovascular Patients

Complications in anticoagulation therapy and long term consequences of the post thrombotic syndromes requires a fast and powerful therapy such as heparin therapy (anticoagulation) to minimize the thrombotic effects in patients. Thus, a simple approach via electrochemical method: Differential pulse polarography (DPP) has been developed for heparin analysis as a powerful clinical tool to monitor anticoagulation action in-patient undergoing heparin therapy. The method has been standardized for determination of heparin activity over the existing methods and a very well defined characteristic reduction peak at −1.25 V in 2 M NaOH was observed for heparin. A linear relation was observed with a regression equation as y = 0.3117x + 0.8069, for 0.1 to 2.0 units/ml heparin. The developed DPP method was observed with excellent precision, accuracy and recovery in human blood plasma samples and in pharmacological formulations. The limit of detection (LOD) and limit of quantification (LOQ) noticed to be 2.04 and 6.8 units/ml respectively. The DPP results compared with pharmacological screening through average thrombin time (TT) and applied to monitor invitro anticoagulation action of heparin in healthy human subjects. Statistical analysis done to validate developed DPP method for heparin analysis and its probable clinical use to monitor anticoagulation action to treat patients suffering from various cerebrovascular disorders (CVD) by proper dosing of heparin.