Nonvalvular Atrial Fibrillation Subjects Research Articles

Measurement of apixaban concentrations in different human biological fluids by UHPLC-MS/MS. Clinical pharmacokinetic application in a subject with chronic kidney disease and nonvalvular atrial fibrillation on haemodialysis

BackgroundApixaban’s technical sheet does not recommend its use in clinical practice for patients with chronic kidney disease undergoing haemodialysis. However, recent studies indicate that apixaban could be a safe oral anticoagulant in these kinds of patients who do not present valvular atrial fibrillation. We developed and validated ultra–high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS) procedures for measuring apixaban concentrations in plasma, dialysate liquid, and urine. Material and methodsSimple protein precipitation was implemented to prepare samples. Chromatographic separations were achieved on an Acquity®-UPLC®-BEHTM (2.1x100 mm id, 1.7 µm) reverse-phase C18 column using a water/acetonitrile non-linear gradient containing 0.1 % formic acid at a 0.4 mL/min flow rate. Apixaban and its internal standard (apixaban-d3) were detected by electrospray ionisation mass spectrometry in positive and multiple reaction monitoring modes, using transitions of 460.3 → 199.0/443.2 and 463.3 → 202.0, respectively. ResultsNo significant interferences and carry-overs were observed. Precisions, absolute relative biases, normalised-matrix factors, and normalised recoveries were ≤ 12.2%, ≤8.0%, 94.3–105.1%, and 93.9–105.4%, respectively. Linearity was observed between 5 and 500 μg/L for plasma/dialysate liquid and 5–1000 μg/L for urine. ConclusionsThe validated UHPLC-MS/MS procedures could help support a pharmacokinetic study in non-valvular atrial fibrillation subjects with chronic kidney disease undergoing haemodialysis and apixaban-based anticoagulant therapy.

The rs2108622 polymorphism is related to the early risk of ischemic stroke in non-valvular atrial fibrillation subjects under oral anticoagulation.

Oral anticoagulant treatments, such as vitamin K antagonists (VKAs), are the main treatments administered to atrial fibrillation (AF) patients in order to prevent ischemic stroke (IS). However, the genes involved in the VKA metabolism can undergo variations in a single nucleotide (SNP). These SNPs may then affect the VKA target enzyme (VKORC1), VKA degradation enzyme (CYP2C9), and vitamin K bioavailability enzyme (CYP4F2). We genotyped these SNPs in a cohort of patients with non-valvular AF who were under VKA treatment after suffering an IS. Clinical variables, CHADS2-VASC score and data about the international normalized ratio (INR) within the therapeutic range were all recorded. DNA was extracted from blood and genotyping was carried out by DNA sequencing. The main endpoint was the time from VKA onset to IS. Of a total of 356 consecutive IS patients monitored, 33 were included in the study. The median time to the event was 2248.0 days (interquartile range [IQR] 896.3-3545.3). The median CHADS2-VASC score was 4.0 (IQR 3.0-6.0). When we considered the risk of IS within 2 years under VKA treatment, we found that only the rs2108622 AA genotype was significantly associated with this endpoint (early IS) (hazard ratio 6.81, 95% CI 1.37-33.92, p = 0.019). Kaplan-Meier curve analysis also showed a significant relationship between early IS and rs2108622 AA genotype (Log rank p = 0.022). The CYP4F2 gene rs2108622 polymorphism was associated with a risk of early IS in NV-AF patients under VKA treatment.

Abstract 152: Adherence to Rivaroxaban versus Apixaban Among Patients With Atrial Fibrillation: Analysis of Overall Population and Subgroups of Prior Oral Anticoagulant Users

Background: Medication nonadherence predicts poor outcomes among patients with non-valvular atrial fibrillation (NVAF). Understanding differences in adherence rates among non-vitamin K oral anticoagulants (NOACs) could guide treatment decisions, promote adherence and improve clinical outcomes. Objective: To compare adherence to rivaroxaban and apixaban among the overall NVAF population and subgroups at higher risk for adverse clinical outcomes (e.g., prior OAC use, multiple comorbidities, and with risk factors for nonadherence). Methods: Using healthcare claims from the Truven Health Analytics MarketScan database from 7/2012-7/2015, adult patients with 2 dispensings of rivaroxaban or apixaban at least 180 days apart, with > 60 days of supply, ≥ 6 months of pre- and post-index eligibility, ≥ 2 atrial fibrillation diagnoses pre- or post-index, and without valvular involvement were identified. Propensity score methods were used to create matched cohorts of rivaroxaban and apixaban patients, adjusting for demographics, risk factors for nonadherence (e.g., bipolar, anxiety), previous OAC use, and clinical characteristics. Adherence was assessed using the percentage of patients with proportion of days covered ≥0.8 at 6 months. Subgroups of patients with prior OAC use, prior OAC use and a Quan-Charlson Comorbidity index ≥2, and prior OAC use with/without nonadherence risk factors were evaluated. Results: 14,635 NVAF subjects were included in each of 2 matched cohorts. All baseline characteristics were balanced between cohorts. At 6 months, significantly more rivaroxaban users were adherent to treatment as compared to apixaban users (82.4% vs 78.5%; absolute difference of 3.9%; P<0.01). Rivaroxaban users had significantly higher adherence rates in all subgroups examined with prior OAC agents (Figure). Conclusion: Rivaroxaban users had consistently higher adherence rates than apixaban users overall and among all NVAF subgroups examined.

New Oral Anticoagulants in Nonvalvular Atrial Fibrillation.

The choice of an oral anticoagulant (OAC) for patients with nonvalvular atrial fibrillation (NVAF) is a major and complex clinical decision taking into account the individual risk-benefit ratio and bearing in mind the chronicity of therapy. This review focuses on the safety and efficacy of new oral anticoagulants (NOACs) compared with conventional vitamin K antagonists (VKA) in patients with NVAF. Current data suggest that NOACs are at least as effective and safe as VKAs for most NVAF subjects. The NOACs do not mandate dietary restrictions and regular pharmacodynamic monitoring, and they seem to have lesser incidence of intracranial or fatal bleeding when compared with VKAs. However, both dabigatran 150 twice daily and rivaroxaban have a slightly higher incidence of gastrointestinal bleeding when compared with VKAs. The article will delineate the current knowledge as well as scientific gaps related to the choice and dosage of anticoagulation regimens for various NVAF subsets and will address certain common clinical scenarios requiring special considerations. The article also addresses the shortcomings of NOACs: lack of therapeutic pharmacokinetic and pharmacodynamic targets, absence of tools to assess compliance and efficacy, rigid and limited dosage options, and absence of effective and inexpensive reversal agents.

Coronary Artery Disease, Left Ventricular Hypertrophy and Diastolic Dysfunction are Associated with Stroke in Patients Affected by Persistent Non-Valvular Atrial Fibrillation: A Case-Control Study

Persistent non-valvular atrial fibrillation (NVAF) is associated with an increased risk of cardiovascular events such as stroke, and its rate is expected to rise because of the ageing population. The absolute rate of stroke depends on age and comorbidity. Risk stratification for stroke in patients with NVAF derives from populations enrolled in randomized clinical trials. However, participants in clinical trials are often not representative of the general population. Many stroke risk stratification scores have been used, but they do not include transthoracic echocardiogram (TTE), pulsate wave Doppler (PWD) and tissue Doppler imaging (TDI), simple and non- invasive diagnostic tools. The role of TTE, PWD and TDI findings has not been previously determined. Our study goal was to determine the association between TTE and PWD findings and stroke prevalence in a population of NVAF prone outpatients.Patients were divided into two groups: P for stroke prone and F for stroke free. There were no statistically significant differences between the two groups concerning cardiovascular risk factors, age (p=0.2), sex (p=0.2), smoking (p=0.3), diabetes (p=0.1) and hypercholesterolemia (p=0.2); hypertension was statistically significant (p<0.001). There were statistically significant differences concerning coronary artery disease, previous acute myocardial infarction (AMI) (p<0.05) and non- AMI coronaropathy (p<0.04), a higher rate being in the P group. Concerning echo-Doppler findings, a higher statistically significant rate of left ventricular hypertrophy (LVH) (p<0.05) and left ventricular diastolic dysfunction (p<0.001) was found in the P group and dilated left atrium (p<0.04) in the F group, the difference was not significant for mitral regurgitation (p=0.7). Stroke prone NVAF patients have a higher rate of hypertension, coronary artery disease, with and without AMI, LVH and left ventricular diastolic dysfunction, but not left atrial dilatation. M-B mode echocardiography and PWD examination help to identify high-risk stroke patients among NVAF subjects; therefore, they may help in the selection of appropriate therapy for each patient.

Asymptomatic embolisation in non-valvular atrial fibrillation and its relationship to anticoagulation therapy

Objective: A prospective study to determine the prevalence of embolic signals (ES) detected with transcranial Doppler ultrasound (TCD) in subjects with non-valvular atrial fibrillation (NVAF) who were and were not taking anticoagulants. Methods: Sixty-eight subjects with NVAF taking warfarin and sixty-three NVAF subjects not taking warfarin were recruited from the cardiology department. No patients had suffered a previous stroke or clinical systemic embolisation. Thirty subjects in sinus rhythm were recruited as controls. TCD recordings were performed bilaterally from the middle cerebral arteries for 1 h. In 126 subjects (96%) the recording was repeated 1 week later. All Doppler recordings were reviewed blindly by an observer for ES. Results: After one recording ES were detected in one warfarin NVAF subject (1.5%), four non-warfarin NVAF subjects (6.3%) and no sinus rhythm controls. Following both recordings ES were detected in one warfarin NVAF subject (1.5%) and seven non-warfarin NVAF subjects (11.9%) P=0.017. Conclusions: Asymptomatic ES can be detected in a minority of subjects with NVAF. These signals were significantly less common in NVAF subjects taking warfarin, and this is consistent with asymptomatic ES having clinical significance in this disease. TCD detection of ES may have application in patients with NVAF for risk stratification, and assessment of the efficacy of new anti-platelet and anti-thrombotic regimens in the condition. Further large prospective studies are required to determine whether ES predict stroke risk in this patient group.

Asymptomatic embolization in subjects with atrial fibrillation not taking anticoagulants: a prospective study.

Embolism is believed to be the major cause of stroke in patients with nonvalvular atrial fibrillation (NVAF). The detection of asymptomatic embolic signals (ES) in individuals with NVAF might allow identification of patients at high risk of stroke and monitoring of therapy in individual subjects. We determined the frequency of asymptomatic ES in patients with NVAF who were not taking warfarin. Bilateral transcranial Doppler recordings were made for 1 hour from the middle cerebral arteries of 111 successive patients with NVAF taking aspirin alone or no antithrombotic or anticoagulant therapy. Adequate recordings could be made in 86 patients. In 79 subjects, recordings were performed on a second occasion to study temporal variability. Recordings for a single hour were also made in 30 age-matched control subjects. ES were detected in 13 (15.1%) of NVAF subjects but in no control subjects (P=0.02). ES were detected both in subjects with symptomatic NVAF (4 of 30 [13.1%], P=0.04 versus controls) and asymptomatic NVAF (9 of 56 [16.1%], P=0.02 versus controls). There was no correlation between the presence of ES and smoking status, diabetes, hypertension, aspirin use, aspirin dose, symptomatic status, left atrial size, left ventricular function, or the presence of left atrial thrombus detected on transthoracic echocardiography. Repeating the recording increased the number of patients with ES to 21 (26.6%). On considering the results of both recordings, again there was no association for either recording between the presence of ES and smoking status, diabetes, hypertension, aspirin use, aspirin dose, age, symptomatic status, left atrial size, or left ventricular function. On repeating the recording, in the symptomatic group only 2 patients (8%) changed status, in contrast to 15 (29%) in the asymptomatic group. ES can be detected in patients with NVAF at a low frequency. Particularly in asymptomatic patients, ES show marked temporal variability. We found no correlation between the presence of previously reported clinical and echocardiographic markers of increased stroke risk and the presence of ES. This association requires further investigation before the clinical utility of this technique in patients with NVAF is decided.