-
JAMA Network Open Nov 2023There are no data on patient-centered outcomes and health care costs by frailty in patients with atrial fibrillation (AF) taking oral anticoagulants (OACs).
IMPORTANCE
There are no data on patient-centered outcomes and health care costs by frailty in patients with atrial fibrillation (AF) taking oral anticoagulants (OACs).
OBJECTIVE
To compare home time, clinical events, and health care costs associated with OACs by frailty levels in older adults with AF.
DESIGN, SETTING, AND PARTICIPANTS
This community-based cohort study assessed Medicare fee-for-service beneficiaries 65 years or older with AF from January 1, 2013, to December 31, 2019. Data analysis was performed from January to December 2022.
EXPOSURES
Apixaban, rivaroxaban, and warfarin use were measured from prescription claims. Frailty was measured using a validated claims-based frailty index.
MAIN OUTCOMES AND MEASURES
Outcome measures were (1) home time (days alive out of the hospital and skilled nursing facility) loss greater than 14 days; (2) a composite end point of ischemic stroke, systemic embolism, major bleeding, or death; and (3) total cost per member per year after propensity score overlap weighting.
RESULTS
The weighted population comprised 136 551 beneficiaries, including 45 950 taking apixaban (mean [SD] age, 77.6 [7.3] years; 51.3% female), 45 320 taking rivaroxaban (mean [SD] age, 77.6 [7.3] years; 51.9% female), and 45 281 taking warfarin (mean [SD] age, 77.6 [7.3] years; 52.0% female). Compared with apixaban, rivaroxaban was associated with increased risk of home time lost greater than 14 days (risk difference per 100 persons, 1.8 [95% CI, 1.5-2.1]), composite end point (rate difference per 1000 person-years, 21.3 [95% CI, 16.4-26.2]), and total cost (mean difference, $890 [95% CI, $652-$1127]), with greater differences among the beneficiaries with frailty. Use of warfarin relative to apixaban was associated with increased home time lost (risk difference per 100 persons, 3.2 [95% CI, 2.9-3.5]) and composite end point (rate difference per 1000 person-years, 29.4 [95% CI, 24.5-34.3]), with greater differences among the beneficiaries with frailty. Compared with apixaban, warfarin was associated with lower total cost (mean difference, -$1166 [95% CI, -$1396 to -$937]) but higher cost when excluding OAC cost (mean difference, $1409 [95% CI, $1177 to $1642]) regardless of frailty levels.
CONCLUSIONS AND RELEVANCE
In older adults with AF, apixaban was associated with increased home time and lower rates of clinical events than rivaroxaban and warfarin, especially for those with frailty. Apixaban was associated with lower total cost compared with rivaroxaban but higher cost compared with warfarin due to higher OAC cost. These findings suggest that apixaban may be preferred for older adults with AF, particularly those with frailty.
Topics: United States; Humans; Aged; Female; Male; Atrial Fibrillation; Warfarin; Rivaroxaban; Cohort Studies; Frailty; Medicare; Anticoagulants; Health Care Costs
PubMed: 37943558
DOI: 10.1001/jamanetworkopen.2023.42264 -
Swiss Medical Weekly Jul 2023Anticoagulants are essential in preventing and treating thrombosis. Unfortunately, their use is accompanied by an enhanced risk of bleeding. Since the introduction of...
Recommendations for the use of andexanet alfa in the management of bleeding in patients on oral factor Xa inhibitors in Switzerland: Guideline from the Working Party Hemostasis of the Swiss Society of Hematology.
Anticoagulants are essential in preventing and treating thrombosis. Unfortunately, their use is accompanied by an enhanced risk of bleeding. Since the introduction of direct oral anticoagulants (DOACs), the risk of major bleeding has been reduced but not eliminated. Major bleeding events related to the use of factor Xa inhibitors can be challenging to manage. In recent years, four-factor prothrombin complex concentrates have been used in patients with severe bleeding taking oral direct factor Xa inhibitors (apixaban, edoxaban and rivaroxaban). Andexanet alfa (OndexxyaTM, AstraZeneca AG) is a specially designed recombinant version of human factor Xa that acts as a decoy receptor to reverse the effects of factor Xa inhibitors. Since 2 December 2020, andexanet alfa has been used in Switzerland for adult patients receiving apixaban or rivaroxaban when reversal of anticoagulation is required because of life-threatening or uncontrolled bleeding. However, the use of andexanet alfa remains a challenge owing to its cost, the reported thrombotic complications and the fact that its efficacy mainly relates to intracranial haemorrhage. Moreover, the use of nonspecific reversal agents together with andexanet alfa is controversial. The present recommendations on the use of andexanet alfa in the management of bleeding in patients on factor Xa inhibitors in Switzerland were developed by a group of Swiss experts from the Working Party Hemostasis of the Swiss Society of Hematology. These recommendations aim to provide support to clinicians in their decision-making in the management of patients with major bleeding receiving factor Xa inhibitors.
Topics: Adult; Humans; Factor Xa Inhibitors; Factor Xa; Rivaroxaban; Switzerland; Hemorrhage; Anticoagulants
PubMed: 37499160
DOI: 10.57187/smw.2023.40113 -
Human Genomics Jul 2023The influence of genetic factors on the pharmacokinetics and clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) is poorly...
BACKGROUND
The influence of genetic factors on the pharmacokinetics and clinical outcomes of rivaroxaban in patients with non-valvular atrial fibrillation (NVAF) is poorly understood. This study aimed to explore the effects of CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms on the trough concentrations and the bleeding risk of rivaroxaban in NVAF patients.
PATIENTS AND METHODS
This study is a prospective multicenter study. The patient's blood samples were collected to detect the steady-state trough concentrations of rivaroxaban and gene polymorphisms. We visited the patients regularly at month 1, 3, 6, and 12 to record bleeding events and medications.
RESULTS
A total of 95 patients were enrolled in this study, and 9 gene loci were detected. For the dose-adjusted trough concentration ratio (C/D) of rivaroxaban, the homozygous mutant type was significantly lower than wild type at ABCB1 rs4148738 locus (TT vs. CC, P = 0.033), and the mutant type was significantly lower than the wild type at ABCB1 rs4728709 locus (AA + GA vs. GG, P = 0.008). ABCB1 (rs1045642, rs1128503), CYP3A4 (rs2242480, rs4646437), CYP3A5 (rs776746), and ABCG2 (rs2231137, rs2231142) gene polymorphisms had no significant effect on the C/D of rivaroxaban. For the bleeding events, we found that there were no significant differences among genotypes of all gene loci.
CONCLUSION
This study found for the first time that ABCB1 rs4148738 and rs4728709 gene polymorphisms had a significant impact on the C/D of rivaroxaban in NVAF patients. CYP3A4/5, ABCB1, and ABCG2 gene polymorphisms were not associated with the bleeding risk of rivaroxaban.
Topics: Humans; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Atrial Fibrillation; Cytochrome P-450 CYP3A; Neoplasm Proteins; Polymorphism, Genetic; Prospective Studies; Rivaroxaban
PubMed: 37420302
DOI: 10.1186/s40246-023-00506-3 -
Circulation Journal : Official Journal... Aug 2023The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients... (Observational Study)
Observational Study
BACKGROUND
The incidence of venous thromboembolism (VTE; pulmonary embolism [PE] and/or deep vein thrombosis [DVT]) in Japan is increasing, but relatively small numbers of patients from Japan have been included in studies investigating rivaroxaban (a direct factor Xa inhibitor) for the treatment of VTE and preventing its recurrence.Methods and Results: An open-label, prospective, observational study (XASSENT [NCT02558465]) investigated the safety profile and effectiveness of rivaroxaban for ≤2 years in the treatment of VTE and prevention of its recurrence in Japanese clinical practice. Primary outcomes were major bleeding and symptomatic recurrent VTE. Statistical analyses were exploratory and descriptive. Overall, 2,540 patients were enrolled (safety analysis population [SAP], n=2,387; effectiveness analysis population [EAP], n=2,386). In the SAP, >80% of patients received the approved rivaroxaban dose, the mean (standard deviation) age was 66.6 (15.0) years, ≈74% were >50 kg, and 43% had a creatinine clearance ≥80 mL/min. PE+DVT, PE only, and DVT only were reported in 42%, 8%, and 50% of patients, respectively, and active cancer in 17% of patients. Major bleeding was reported in 69 patients (2.89%; 3.60%/patient-year; SAP) and symptomatic PE/DVT recurrence in 26 patients (1.09%; 1.36%/patient-year; EAP) during the treatment period.
CONCLUSIONS
XASSENT provided information on the expected proportions of bleeding and VTE recurrence during rivaroxaban treatment in Japanese clinical practice; no new concerns of safety or effectiveness were found.
Topics: Humans; Aged; Rivaroxaban; Venous Thromboembolism; Anticoagulants; Japan; Prospective Studies; Treatment Outcome; Pulmonary Embolism; Hemorrhage; Product Surveillance, Postmarketing
PubMed: 37245989
DOI: 10.1253/circj.CJ-23-0104 -
Polish Archives of Internal Medicine Aug 2023Isolated distal deep vein thrombosis (IDDVT) is a frequent manifestation of venous thromboembolism (VTE), accounting for up to 50% cases of lower‑extremity deep vein... (Review)
Review
Isolated distal deep vein thrombosis (IDDVT) is a frequent manifestation of venous thromboembolism (VTE), accounting for up to 50% cases of lower‑extremity deep vein thrombosis (DVT). As compared with proximal DVT, IDDVT is more frequently associated with transient risk factors and less often occurs unprovoked or in the presence of permanent risk factors. IDDVT generally carries a significantly lower risk of proximal extension, post‑thrombotic syndrome, and recurrence than proximal DVT. Nevertheless, some patient subgroups, such as those with active cancer, other predisposing permanent risk factors, prior VTE, unprovoked IDDVT, persistently restricted mobility, and trifurcation or bilateral involvement, exhibit a non‑negligible recurrence risk. Unlike in proximal DVT, the optimal therapeutic management of IDDVT remains uncertain. In clinical practice, the vast majority of IDDVT patients are managed with anticoagulation rather than with surveillance serial compression ultrasonography, which tends to be reserved to individuals at a high bleeding risk. Available data seem to favor anticoagulant therapy over no anticoagulation, thanks to a significant reduction in the risk for proximal extension and recurrence, without increased bleeding risk. Recent results of the RIDTS (Rivaroxaban for the Treatment of Symptomatic Isolated Distal Deep Vein Thrombosis) randomized clinical trial with rivaroxaban further support the use of anticoagulant therapy for 3 months over shorter durations (eg, ≤6 weeks). In this review, we offer an updated overview of the epidemiology, risk factors, and clinical course of IDDVT, with a focus on the therapeutic management in light of current guideline recommendations and most recent evidence. We also present real‑life clinical cases of IDDVT with proposed therapeutic approaches, and highlight major challenges and gaps in this field.
Topics: Humans; Venous Thromboembolism; Rivaroxaban; Recurrence; Venous Thrombosis; Anticoagulants; Hemorrhage; Randomized Controlled Trials as Topic
PubMed: 37548526
DOI: 10.20452/pamw.16543 -
Frontiers in Pharmacology 2023Almonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for non-small cell...
Almonertinib, a third-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), is commonly used as a first-line treatment for non-small cell lung cancer (NSCLC) patients with EGFR T790M mutations. Rivaroxaban and apixaban are a selective, direct factor Xa inhibitor used to treat venous thromboembolism (VTE), which is a frequent complication of NSCLC. Rivaroxaban and apixaban are substrates of CYP3A4, P-gp and BCRP, whereas almonertinib is an inhibitor of P-gp and BCRP. Rivaroxaban or apixaban are often prescribed together with almonertinib in NSCLC patients, but clear information on pharmacokinetic drug interaction is lacking. Therefore, this study aimed to unravel the extent of interactions between almonertinib-rivaroxaban and almonertinib apixaban in rats, and whether the pharmacokinetic interaction can be mitigated by rivaroxaban and apixaban dose adjustment. Rats were divided into ten groups ( = 6) that received rivaroxaban (2 mg/kg) (group 1), apixaban (0.5 mg/kg) (group 2), almonertinib (15 mg/kg) (group 3, group 4), almonertinib with rivaroxaban (2 mg/kg) (group 5), almonertinib with rivaroxaban (1 mg/kg) (group 6), almonertinib with apixaban (0.5 mg/kg) (group 7), almonertinib with apixaban (0.25 mg/kg) (group 8), rivaroxaban (2 mg/kg) with almonertinib (group 9), apixaban (0.5 mg/kg) with almonertinib (group 10). The concentrations of drugs were determined by an ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). The levels of messenger RNA were determined using quantitative real-time polymerase chain reaction (qRT-PCR). The results indicate that almonertinib increased the C and AUC of 2 mg/kg rivaroxaban by 3.30 and 3.60-fold, 1 mg/kg rivaroxaban by 1.28 and 1.90-fold. Almonertinib increased the C and AUC of 0.5 mg/kg apixaban by 2.69 and 2.87-fold, 0.25 mg/kg apixaban by 2.19 and 2.06-fold. In addition, rivaroxaban also increased systemic exposure to almonertinib. The results of qRT-PCR showed that almonertinib reduced the expression of Cyp3a1 in liver and intestine, and Abcb1a, Abcg2 in intestine and kidney. The pharmacokinetic results suggest that it is important to take special care of the interactions of these drugs in clinical applications.
PubMed: 37860116
DOI: 10.3389/fphar.2023.1263975 -
Annals of Neurology Jul 2023Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected...
BACKGROUND
Atrial fibrillation (AF) known before ischemic stroke (KAF) has been postulated to be an independent category with a recurrence risk higher than that of AF detected after stroke (AFDAS). However, it is unknown whether this risk difference is confounded by pre-existing anticoagulation, which is most common in KAF and also indicates a high ischemic stroke recurrence risk.
METHODS
Individual patient data analysis from 5 prospective cohorts of anticoagulated patients following AF-associated ischemic stroke. We compared the primary (ischemic stroke recurrence) and secondary outcome (all-cause death) among patients with AFDAS versus KAF and among anticoagulation-naïve versus previously anticoagulated patients using multivariable Cox, Fine-Gray models, and goodness-of-fit statistics to investigate the relative independent prognostic importance of AF-category and pre-existing anticoagulation.
RESULTS
Of 4,357 patients, 1,889 (43%) had AFDAS and 2,468 (57%) had KAF, while 3,105 (71%) were anticoagulation-naïve before stroke and 1,252 (29%) were previously anticoagulated. During 6,071 patient-years of follow-up, we observed 244 recurrent strokes and 661 deaths. Only pre-existing anticoagulation (but not KAF) was independently associated with a higher hazard for stroke recurrence in both Cox and Fine-Gray models. Models incorporating pre-existing anticoagulation showed better fit than those with AF category; adding AF-category did not result in better model fit. Neither pre-existing anticoagulation nor KAF were independently associated with death.
CONCLUSION
Our findings challenge the notion that KAF and AFDAS are clinically relevant and distinct prognostic entities. Instead of attributing an independently high stroke recurrence risk to KAF, future research should focus on the causes of stroke despite anticoagulation to develop improved preventive treatments. ANN NEUROL 2023;94:43-54.
Topics: Humans; Atrial Fibrillation; Prospective Studies; Risk Factors; Stroke; Ischemic Stroke; Anticoagulants
PubMed: 36975022
DOI: 10.1002/ana.26654 -
Hamostaseologie Dec 2023For life-threatening or uncontrollable bleeding in association with the thrombin inhibitor dabigatran, the monoclonal antibody fragment idarucizumab is available, and...
BACKGROUND
For life-threatening or uncontrollable bleeding in association with the thrombin inhibitor dabigatran, the monoclonal antibody fragment idarucizumab is available, and for bleeding in association with the direct factor Xa inhibitors rivaroxaban or apixaban, the modified recombinant FXa protein andexanet is available for reversal. These antidotes represent emergency drugs that are typically used only after performing guideline-compliant multimodal measures.
METHODS
An interdisciplinary group of experienced experts in the fields of angiology, hematology, internal medicine, clinical pharmacology, laboratory medicine, transfusion medicine, anesthesiology, intensive care, and hemostaseology developed recommendations relevant to daily clinical practice based on the current scientific evidence.
RESULTS
Reversal of oral anticoagulants should be considered for severe bleeding in the following situations: (1) life-threatening bleeding or refractory hemorrhagic shock, (2) intracerebral bleeding, or (3) endoscopically unstoppable gastrointestinal bleeding. After successful hemostasis, anticoagulation (e.g., direct oral anticoagulant, vitamin K antagonist, and heparin) should be resumed promptly, taking into account individual bleeding and thromboembolic risk.
DISCUSSION
This article aims to facilitate the management of patients with andexanet by all medical disciplines involved, thereby ensuring optimal care of patients during bleeding episodes.
Topics: Humans; Anticoagulants; Hemorrhage; Rivaroxaban; Heparin; Recombinant Proteins; Factor Xa Inhibitors; Administration, Oral
PubMed: 37813368
DOI: 10.1055/a-2136-2391 -
Saudi Pharmaceutical Journal : SPJ :... Aug 2023Since the risk of recurrence of venous thromboembolism (VTE) increases with duration or inadequate anticoagulation dosage, a proper regimen of apixaban and rivaroxaban...
BACKGROUND
Since the risk of recurrence of venous thromboembolism (VTE) increases with duration or inadequate anticoagulation dosage, a proper regimen of apixaban and rivaroxaban is essential in patients with VTE, especially during the acute phase. This study aims to describe the clinical characteristics and dosing of anticoagulants for patients who received apixaban or rivaroxaban for VTE treatment.
METHODS
The multi-center retrospective observational study included patients diagnosed with VTE who had received apixaban or rivaroxaban between January 1, 2016, and December 31, 2021. The study's description of real-world practices includes patients' characteristics, along with anticoagulant dose and duration used for lead-in or maintenance therapy to manage VTE.
RESULTS
The study involved 695 patients with VTE; 342 of whom were treated with apixaban (49.2%), while 353 were treated with rivaroxaban (50.8%). During the acute phase, 30.1% and 19.3% of patients did not receive lead-in therapy with apixaban and rivaroxaban, respectively, and 1.2% received reduced doses of either medication. Among the patients who received apixaban alone for lead-in, the majority (79.5%) received the recommended duration, while 17.1% received a shorter lead-in duration (≤5 days), with an overall mean duration of 6.5 days. Most patients who received rivaroxaban alone for lead-in (93.0%) received the drug for the recommended duration, with an overall mean duration of 20.2 days. Most of the patients who did not receive apixaban or rivaroxaban for lead-in used parenteral anticoagulants for varying durations; however, around 25.0% of these patients did not receive any lead-in anticoagulant and started on maintenance therapy. Overall, patients who did not receive apixaban or rivaroxaban lead-in therapy were commonly associated with a higher risk of bleeding according to their clinical characteristics.
CONCLUSION
A notable proportion of patients with VTE who were mostly at low to intermediate risk of bleeding received non-recommended doses or durations of apixaban or rivaroxaban for lead-in therapy. Large studies are needed to establish evidence about the outcomes associated with these practices.
PubMed: 37576856
DOI: 10.1016/j.jsps.2023.06.006 -
Journal of Thrombosis and Haemostasis :... Aug 2023Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease. (Randomized Controlled Trial)
Randomized Controlled Trial
A randomized controlled trial to investigate the use of acute coronary syndrome therapy in patients hospitalized with COVID-19: the COVID-19 Acute Coronary Syndrome trial.
BACKGROUND
Patients hospitalized with COVID-19 suffer thrombotic complications. Risk factors for poor outcomes are shared with coronary artery disease.
OBJECTIVES
To investigate the efficacy of an acute coronary syndrome regimen in patients hospitalized with COVID-19 and coronary disease risk factors.
METHODS
A randomized controlled, open-label trial across acute hospitals (United Kingdom and Brazil) added aspirin, clopidogrel, low-dose rivaroxaban, atorvastatin, and omeprazole to standard care for 28 days. Primary efficacy and safety outcomes were 30-day mortality and bleeding. The key secondary outcome was a daily clinical status (at home, in hospital, on intensive therapy unit admission, or death).
RESULTS
Three hundred twenty patients from 9 centers were randomized. The trial terminated early due to low recruitment. At 30 days, there was no significant difference in mortality (intervention vs control, 11.5% vs 15%; unadjusted odds ratio [OR], 0.73; 95% CI, 0.38-1.41; p = .355). Significant bleeds were infrequent and were not significantly different between the arms (intervention vs control, 1.9% vs 1.9%; p > .999). Using a Bayesian Markov longitudinal ordinal model, it was 93% probable that intervention arm participants were more likely to transition to a better clinical state each day (OR, 1.46; 95% credible interval [CrI], 0.88-2.37; Pr [beta > 0], 93%; adjusted OR, 1.50; 95% CrI, 0.91-2.45; Pr [beta > 0], 95%) and median time to discharge to home was 2 days shorter (95% CrI, -4 to 0; 2% probability that it was worse).
CONCLUSION
Acute coronary syndrome treatment regimen was associated with a reduction in the length of hospital stay without an excess in major bleeding. A larger trial is needed to evaluate mortality.
Topics: Humans; COVID-19; SARS-CoV-2; Acute Coronary Syndrome; Bayes Theorem; Aspirin; Hemorrhage; Treatment Outcome
PubMed: 37230416
DOI: 10.1016/j.jtha.2023.04.045