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Genetics Research 2023Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify... (Meta-Analysis)
Meta-Analysis Review
INTRODUCTION
Pharmacogenetics is a potential approach that can be applied to decline the burden of rivaroxaban's ADRs. The current systematic review and meta-analysis aim to identify genetic variants correlated with rivaroxaban exposure and evaluate their importance.
METHODS
We systematically searched PubMed, Web of Science, and Scopus databases for all observational and interventional studies. The fixed effect method was used to pool the data when the Q-test's value was higher than 0.1. We used random models when the value was less than 0.1.
RESULTS
Data from ten studies (4721 participants) were analyzed in the current review. Qualitative synthesis from included studies found that two variants of ABCB1 (rs1045642 and rs2032582) and one variant of APOB (rs13306198) are potential contributors to rivaroxaban concentrations. Both wild homozygotes (AA) and heterozygotes (AC) of rs1045642 have significantly lower rivaroxaban concentrations compared to mutated homozygotes (CC) (SMD = 0.516, 95% CI: 0.115 to 0.917; SMD = 0.772, 95% CI: 0.088 to 1.455, respectively). Nevertheless, pooling unadjusted odds ratios did not yield a statistically significant correlation between rivaroxaban ADRs and genetic mutations.
CONCLUSION
This study revealed that being an AC or CC for rs1045642 is attributed to a considerably higher rivaroxaban level in participants using rivaroxaban. That is to say, rs1045642 is a remarkable predictor of rivaroxaban metabolism. We concluded that identifying rs1045642 before drug administration might decrease ADRs although further studies adjusted for potential confounders are strongly suggested.
Topics: Humans; Rivaroxaban; Pharmacogenetics; Homozygote; Heterozygote; Drug-Related Side Effects and Adverse Reactions
PubMed: 37942082
DOI: 10.1155/2023/6105320 -
Clinical and Applied... 2024Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though... (Review)
Review
Direct oral anticoagulants (DOACs) exert anticoagulation effect by directly inhibiting Factor Xa (rivaroxaban, apixaban, and edoxaban) or thrombin (dabigatran). Though DOACs are characterized by fixed-dose prescribing and generally do not require routine laboratory drug-level monitoring (DLM), circumstances may arise where the DLM may aid in clinical decision-making, including DOAC dose adjustment, anticoagulant class change, or decisions to withhold or administer reversal agents. We review the current literature that describes high-risk patient groups in which DLM may be beneficial for improved patient anticoagulation management and stewardship. The review also summarizes the limitations of conventional coagulation testing and discuss the emerging utility of quantitative methods for routine and rapid emergent evaluation of DOAC drug levels-in particular, the Anti-Xa activity to detect Factor Xa Inhibitors (rivaroxaban, apixaban, and edoxaban). Both technical and regulatory barriers to widespread DLM implementation are limiting factors to further clinical research that must be overcome, in order to propose universal DOAC DLM strategies and provide clinical-laboratory correlation to formally classify high-risk patient groups.
Topics: Humans; Administration, Oral; Anticoagulants; Drug Monitoring; Factor Xa Inhibitors; Blood Coagulation Tests
PubMed: 38650302
DOI: 10.1177/10760296241241524 -
Cureus Apr 2024The objective of this network meta-analysis was to assess the efficacy and safety of apixaban, dabigatran, rivaroxaban, and edoxaban in patients diagnosed with atrial... (Review)
Review
Comparison of Effectiveness and Safety of Apixaban, Dabigatran, and Rivaroxaban in Patients With Valvular Atrial Fibrillation: A Network Meta-Analysis of Randomized-Control Trials and Observational Studies.
The objective of this network meta-analysis was to assess the efficacy and safety of apixaban, dabigatran, rivaroxaban, and edoxaban in patients diagnosed with atrial fibrillation and valvular heart disease. A comprehensive search was conducted across various electronic databases, including PubMed, Embase, and Web of Science, from inception to February 15, 2024. The search strategy utilized a combination of medical subject headings (MeSH) terms and relevant keywords related to valvular heart disease, atrial fibrillation, anticoagulant therapy, and study design, such as randomized controlled trials and observational studies. The outcomes evaluated in this analysis comprised the incidence of stroke or systemic embolism (SE), as well as the occurrences of major bleeding events. A total of 10 studies were incorporated into this meta-analysis, encompassing 40,662 participants. Of these, 12,385 received apixaban, 2,829 received dabigatran, 13,662 received rivaroxaban, 2,582 received edoxaban, and 9,202 received warfarin. The duration of follow-up in the included studies ranged from 3 to 54 months. Among the four direct oral anticoagulants (DOACs) studied, apixaban demonstrated a significant reduction in the risk of stroke or SE when compared to other DOACs and warfarin, highlighting its efficacy in patients with atrial fibrillation and valvular heart disease. Additionally, apixaban exhibited a lower risk of major bleeding events, further emphasizing its favorable safety profile compared to the other agents assessed. In conclusion, our findings suggest that apixaban may be more effective and safer than other DOACs and warfarin in this patient population. However, additional studies are warranted to compare the various DOACs in this cohort to identify the optimal treatment strategy for preventing adverse outcomes.
PubMed: 38707166
DOI: 10.7759/cureus.57656 -
Drug Design, Development and Therapy 2023Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance...
PURPOSE
Direct oral anticoagulants (DOACs) are widely used for stroke prevention in atrial fibrillation. However, they have a bleeding complication. Breast cancer resistance protein, encoded by , is known to be an efflux transporter of apixaban and rivaroxaban among DOACs. This study aimed to investigate the association between gene variants and bleeding complications during treatment with ABCG2 substrates (apixaban and rivaroxaban).
PATIENTS AND METHODS
Patients treated with apixaban and rivaroxaban were enrolled from June 2018 to December 2021. Five single nucleotide polymorphisms (SNPs) of were selected. Previously studied genes (, and ) were further analyzed as possible confounders. Finally, a total of 16 SNPs were examined in this case-control study. The outcome was defined as major bleeding and clinically relevant non-major bleeding. Two models were constructed using the multivariable analysis.
RESULTS
Among 293 patients, 64 were cases. The mean age of the patients was 68.8 years, and males comprised 62.5% of the study population. Model I revealed that a history of bleeding, concurrent use of proton pump inhibitor (PPI), rs3114018, and rs1045642 were significantly associated with bleeding complications; the AORs (95% CI) were 6.209 (2.210-17.442), 2.385 (1.064-5.349), 2.188 (1.156-4.142), and 3.243 (1.371-7.671), respectively. Model II showed that modified HAS-BLED score, concurrent use of PPI, rs3114018, and rs1045642 were significantly associated with bleeding complications.
CONCLUSION
The modified HAS-BLED score, a history of bleeding, concurrent use of PPI, rs3114018, and rs1045642 were significantly associated with the risk of bleeding complications in patients on apixaban and rivaroxaban, after adjusting for other confounders. These findings can be used to develop individualized treatment strategies for patients taking apixaban and rivaroxaban.
Topics: Male; Humans; Aged; Female; Rivaroxaban; ATP Binding Cassette Transporter, Subfamily G, Member 2; Case-Control Studies; Neoplasm Proteins; Polymorphism, Single Nucleotide
PubMed: 37641689
DOI: 10.2147/DDDT.S417096 -
American Journal of Cardiovascular... Jan 2024Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial... (Clinical Trial)
Clinical Trial
BACKGROUND
Rivaroxaban 2.5 mg twice daily with aspirin 100 mg daily was shown to be better than aspirin 100 mg daily for preventing cardiovascular (CV) death, stroke or myocardial infarction in patients with either stable coronary artery disease (CAD) or peripheral artery disease (PAD). The cost-effectiveness of this regimen in this population is essential for decision-makers to know.
METHODS
US direct healthcare system costs (in USD) were applied to hospitalized events, procedures and study drugs utilized by all patients. We determined the mean cost per participant for the full duration of the trial (mean follow-up of 23 months) plus quality-adjusted life years (QALYs) and the incremental cost-effectiveness ratio (ICER) over a lifetime using a two-state Markov model with 1-year cycle length. Sensitivity analyses were performed on the price of rivaroxaban and the annual discontinuation rate.
RESULTS
The costs of events and procedures were reduced for Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) patients who received rivaroxaban 2.5 mg orally (BID) plus acetylsalicylic acid (ASA) compared with ASA alone. Total costs were higher for the combination group ($7426 versus $4173) after considering acquisition costs of the study drug. Over a lifetime, patients receiving rivaroxaban plus ASA incurred $27,255 more and gained 1.17 QALYs compared with those receiving ASA alone resulting in an ICER of $23,295/QALY. ICERs for PAD only and polyvascular disease subgroups were lower.
CONCLUSION
Rivaroxaban 2.5 mg BID plus ASA compared with ASA alone was cost-effective (high value) in the USA. COMPASS ClinicalTrials.gov identifier: NCT01776424.
Topics: Humans; Aspirin; Cost-Benefit Analysis; Drug Therapy, Combination; Factor Xa Inhibitors; Myocardial Infarction; Peripheral Arterial Disease; Rivaroxaban; Stroke
PubMed: 38153624
DOI: 10.1007/s40256-023-00620-6 -
Cardiovascular Therapeutics 2023Optimal antithrombotic therapy during the chronic maintenance period in patients with coronary artery disease (CAD) is unknown. We compared five kinds of mainstream... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Optimal antithrombotic therapy during the chronic maintenance period in patients with coronary artery disease (CAD) is unknown. We compared five kinds of mainstream chronic maintenance antithrombotic strategies at least one year after the acute phase: aspirin alone, clopidogrel alone, ticagrelor alone, continued dual antiplatelet therapy (DAPT) for a period of time, and maintenance with aspirin combined with a low-dose anticoagulant such as rivaroxaban.
METHODS
Ten randomized, controlled trials were selected using PubMed, Ovid MEDLINE, Embase, and Cochrane library through February 2023. The primary outcome was main adverse cardiac events (MACEs), and secondary outcomes include net adverse clinical events (NACEs), cardiac death, all-cause death, ischemic stroke, stent thrombosis, total bleeding, and major bleeding. A network meta-analysis was conducted with a random-effects model. Data extraction was performed by three independent reviewers.
RESULTS
Our search identified ten eligible randomized controlled trials enrolling a total of 82,084 patients comparing different chronic maintenance antithrombotic strategies. As for the primary endpoint, there was no statistical difference in MACE outcomes between any two of the five methods. As for the secondary endpoint, there was no statistical difference in NACE, major bleeding, all-cause death, cardiac death, and stent thrombosis between any two methods. The aspirin plus low-dose rivaroxaban group had a lower incidence of ischemic stroke compared to the aspirin group (OR = 0.49, 95% CrI 0.26-0.91). And the prolonged DAPT group had a higher total bleeding rate compared to aspirin group (OR = 2.4, 95% CrI 1.1-5.9).
CONCLUSIONS
In terms of MACE, NACE, all-cause death, cardiac death, stent thrombosis, and major bleeding, there were no significant differences between using aspirin alone, clopidogrel alone, and ticagrelor alone; extending DAPT duration; and using aspirin combined with low-dose rivaroxaban for chronic maintenance antithrombotic regimens. However, choosing aspirin combined with low-dose rivaroxaban can reduce the incidence of ischemic stroke, and prolonged DAPT may have a higher rate of total bleeding. However, it is important to note that this study is based on indirect comparisons, and there is currently a lack of direct evidence comparing various maintenance antiplatelet therapy regimens. Further high-quality studies are needed to address this gap and provide more conclusive evidence on the comparative effectiveness of different maintenance antiplatelet strategies.
Topics: Humans; Coronary Artery Disease; Network Meta-Analysis; Rivaroxaban; Clopidogrel; Fibrinolytic Agents; Platelet Aggregation Inhibitors; Ticagrelor; Ischemic Stroke; Aspirin
PubMed: 37636560
DOI: 10.1155/2023/5446271 -
BMC Medicine Sep 2023Emulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the...
BACKGROUND
Emulating randomized controlled trials (RCTs) by real-world evidence (RWE) studies would benefit future clinical and regulatory decision-making by balancing the limitations of RCT. We aimed to evaluate whether the findings from RWE studies can support regulatory decisions derived from RCTs of non-vitamin K antagonist oral anticoagulants (NOACs) in patients with venous thromboembolism (VTE).
METHODS
Five landmark trials (AMPLIFY, RE-COVER II, Hokusai-VTE, EINSTEIN-DVT, and EINSTEIN-PE) of NOACs were emulated using the South Korean nationwide claims database (January 2012 to August 2020). We applied an active comparator and new-user design to include patients who initiated oral anticoagulants within 28 days from their VTE diagnoses. The prespecified eligibility criteria, exposure (each NOAC, such as apixaban, rivaroxaban, dabigatran, and edoxaban), comparator (conventional therapy, defined as subcutaneous heparin followed by warfarin), and the definition of outcomes from RCTs were emulated as closely as possible in each separate emulation cohort. The primary outcome was identical to each trial, which was defined as recurrent VTE or VTE-related death. The safety outcome was major bleeding. Propensity score matching was conducted to balance 69 covariates between the exposure groups. Effect estimates for outcomes were estimated using the Mantel-Haenszel method and Cox proportional hazards model and subsequently compared with the corresponding RCT estimates.
RESULTS
Compared to trial populations, real-world study populations were older (range: 63-69 years [RWE] vs. 54-59 years [RCT]), with more females (55-60.5% vs. 39-48.3%) and had a higher prevalence of active cancer (4.2-15.4% vs. 2.5-9.5%). The emulated estimates for effectiveness outcomes showed superior effectiveness of NOAC (AMPLIFY: relative risk 0.81, 95% confidence interval 0.70-0.94; RE-COVER II: hazard ratio [HR] 0.60, 0.37-0.96; Hokusai-VTE: 0.49, 0.31-0.78; EINSTEIN-DVT: 0.54, 0.33-0.89; EINSTEIN-PE: 0.50, 0.34-0.74), when contrasted with trials that showed non-inferiority. For safety outcomes, all emulations except for AMPLIFY and EINSTEIN-DVT yielded results consistent with their corresponding RCTs.
CONCLUSIONS
This study revealed the feasibility of complementing RCTs with RWE studies by using claims data in patients with VTE. Future studies to consider the different demographic characteristics between RCT and RWE populations are needed.
Topics: Female; Humans; Administration, Oral; Anticoagulants; Dabigatran; Randomized Controlled Trials as Topic; Rivaroxaban; Venous Thromboembolism; Male; Middle Aged; Aged
PubMed: 37775786
DOI: 10.1186/s12916-023-03069-1 -
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 -
Thrombosis Journal Aug 2023An established treatment strategy for asymptomatic pulmonary embolism (PE) or deep vein thrombosis (DVT) remains uncertain in Japan; therefore, in this study, we clarify...
BACKGROUND
An established treatment strategy for asymptomatic pulmonary embolism (PE) or deep vein thrombosis (DVT) remains uncertain in Japan; therefore, in this study, we clarify the characteristics and outcomes of symptomatic compared to asymptomatic patients with PE or DVT.
METHODS
This prospective, multicenter sub-analysis of the J'xactly study in Japan included 1,016 patients (mean age, 68; 41% male) with venous thromboembolism (VTE) treated with rivaroxaban.
RESULTS
Asymptomatic PE patients (47% of PE patients) were more likely to have active cancer and asymptomatic proximal DVT at lower severity than symptomatic PE patients, despite no differences in age, sex, or the proportion receiving intensive 30 mg/day-rivaroxaban. Patients with asymptomatic DVT (34% of DVT patients) were older, had higher rates of female sex, active cancer, and distal DVT, and received shorter, less intense rivaroxaban treatment. Incidences did not differ between asymptomatic and symptomatic PE patients for recurrent symptomatic VTE (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.22-1.62; P = 0.31) or major bleeding (HR, 0.68; 95% CI, 0.20-2.33; P = 0.58), nor between asymptomatic and symptomatic DVT patients for recurrent symptomatic VTE (HR, 0.56; 95% CI, 0.23-1.40; P = 0.21) and major bleeding (HR, 1.47; 95% CI, 0.54-3.97; P = 0.45).
CONCLUSIONS
The real-world composite adverse event rate for treatment with rivaroxaban, as physician-adjusted for dose and duration, was similar for asymptomatic and symptomatic patients regardless of the presence of PE or DVT, suggesting a favorable safety profile for potential rivaroxaban treatment for asymptomatic VTE.
PubMed: 37599351
DOI: 10.1186/s12959-023-00528-w -
European Journal of Internal Medicine Mar 2024In a large nationwide administrative database including ∼35 % of Italian population, we analyzed the impact of oral anticoagulant treatment (OAT) in patients with a...
INTRODUCTION
In a large nationwide administrative database including ∼35 % of Italian population, we analyzed the impact of oral anticoagulant treatment (OAT) in patients with a hospital diagnosis of non-valvular atrial fibrillation (NVAF).
METHODS AND RESULTS
Of 170404 OAT-naïve patients (mean age 78.7 years; 49.4 % women), only 61.1 % were prescribed direct oral anticoagulants, DOACs, or vitamin-K antagonists, VKAs; 14.2 % were given aspirin (ASA), and 24.8 % no anti-thrombotic drugs (No Tx). We compared ischemic stroke (IS), IS and systemic embolism (IS/SE), intracranial hemorrhage (ICH), major bleeding (MB), major gastro-intestinal bleeding, all-cause deaths and the composite outcome, across four propensity-score matched treatment cohorts with >15400 patients each. Over 2.9±1.5 years, the incidence of IS and IS/SE was slightly less with VKAs than with DOACs (1.62 and 1.84 vs 1.81 and 1.99 events.100 person-years; HR=0.85, 95%CI=0.76-0.95 and HR=0.87, 95%CI=0.78-0.97). This difference disappeared in a sensitivity analysis which excluded those patients treated with low-dose of apixaban, edoxaban, or rivaroxaban (41.7% of DOACs cohort). Compared with DOACs, VKAs were associated with greater incidence of ICH (1.09 vs 0.81; HR=1.38, 95%CI=1.17-1.62), MB (3.78 vs 3.31; HR=1.14, 95%CI=1.02-1.28), all-cause mortality (9.66 vs 10.10; HR=1.07, 95%CI=1.02-1.11), and composite outcome (13.72 vs 13.32; HR=1.04, 95%CI=1.01-1.08). IS, IS/SE, and mortality were more frequent with ASA or No Tx than with VKAs or DOACs (p<0.001 for all comparisons).
CONCLUSIONS
Beyond confirming the association with a better net clinical benefit of DOACs over VKAs, our findings substantiate the large proportion of NVAF patients still inappropriately anticoagulated, thereby reinforcing the need for educational programs.
Topics: Humans; Female; Aged; Male; Atrial Fibrillation; Stroke; Anticoagulants; Rivaroxaban; Ischemic Stroke; Intracranial Hemorrhages; Aspirin; Gastrointestinal Hemorrhage; Administration, Oral; Dabigatran
PubMed: 37879969
DOI: 10.1016/j.ejim.2023.10.010