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Journal of Pharmacokinetics and... Oct 2023Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro...
Enzalutamide is known to strongly induce cytochrome P450 3A4 (CYP3A4). Furthermore, enzalutamide showed induction and inhibition of P-glycoprotein (P-gp) in in vitro studies. A clinical drug-drug interaction (DDI) study between enzalutamide and digoxin, a typical P-gp substrate, suggested enzalutamide has weak inhibitory effect on P-gp substrates. Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban, are dual substrates of CYP3A4 and P-gp, and hence it is recommended to avoid co-administration of these DOACs with combined P-gp and strong CYP3A inducers. Enzalutamide's net effect on P-gp and CYP3A for apixaban and rivaroxaban plasma exposures is of interest to physicians who treat patients for venous thromboembolism with prostate cancer. Accordingly, a physiologically-based pharmacokinetic (PBPK) analysis was performed to predict the magnitude of DDI on apixaban and rivaroxaban exposures in the presence of 160 mg once-daily dosing of enzalutamide. The PBPK models of enzalutamide and M2, a major metabolite of enzalutamide which also has potential to induce CYP3A and P-gp and inhibit P-gp, were developed and verified as perpetrators of CYP3A-and P-gp-mediated interaction. Simulation results predicted a 31% decrease in AUC and no change in C for apixaban and a 45% decrease in AUC and a 25% decrease in C for rivaroxaban when 160 mg multiple doses of enzalutamide were co-administered. In summary, enzalutamide is considered to decrease apixaban and rivaroxaban exposure through the combined effects of CYP3A induction and net P-gp inhibition. Concurrent use of these drugs warrants careful monitoring for efficacy and safety.
Topics: Male; Humans; Cytochrome P-450 CYP3A; Rivaroxaban; Drug Interactions; Pharmaceutical Preparations; Models, Biological
PubMed: 37344637
DOI: 10.1007/s10928-023-09867-7 -
The Cochrane Database of Systematic... Jan 2024Balancing the risk of bleeding and thrombosis after acute myocardial infarction (AMI) is challenging, and the optimal antithrombotic therapy remains uncertain. The... (Meta-Analysis)
Meta-Analysis Review
BACKGROUND
Balancing the risk of bleeding and thrombosis after acute myocardial infarction (AMI) is challenging, and the optimal antithrombotic therapy remains uncertain. The potential of non-vitamin K antagonist oral anticoagulants (NOACs) to prevent ischaemic cardiovascular events is promising, but the evidence remains limited.
OBJECTIVES
To evaluate the efficacy and safety of non-vitamin-K-antagonist oral anticoagulants (NOACs) in addition to background antiplatelet therapy, compared with placebo, antiplatelet therapy, or both, after acute myocardial infarction (AMI) in people without an indication for anticoagulation (i.e. atrial fibrillation or venous thromboembolism).
SEARCH METHODS
We searched CENTRAL, MEDLINE, Embase, the Conference Proceedings Citation Index - Science, and two clinical trial registers in September 2022 with no language restrictions. We checked the reference lists of included studies for any additional trials.
SELECTION CRITERIA
We searched for randomised controlled trials (RCTs) that evaluated NOACs plus antiplatelet therapy versus placebo, antiplatelet therapy, or both, in people without an indication for anticoagulation after an AMI.
DATA COLLECTION AND ANALYSIS
Two review authors independently checked the results of searches to identify relevant studies, assessed each included study, and extracted study data. We conducted random-effects pairwise analyses using Review Manager Web, and network meta-analysis using the R package 'netmeta'. We ranked competing treatments by P scores, which are derived from the P values of all pairwise comparisons and allow ranking of treatments on a continuous 0-to-1 scale.
MAIN RESULTS
We identified seven eligible RCTs, including an ongoing trial that we could not include in the analysis. Of the six RCTs involving 33,039 participants, three RCTs compared rivaroxaban with placebo, two RCTs compared apixaban with placebo, and one RCT compared dabigatran with placebo. All participants in the six RCTs received concomitant antiplatelet therapy. The available evidence suggests that rivaroxaban compared with placebo reduces the rate of all-cause mortality (risk ratio (RR) 0.82, 95% confidence interval (CI) 0.69 to 0.98; number needed to treat for an additional beneficial outcome (NNTB) 250; 3 studies, 21,870 participants; high certainty) and probably reduces cardiovascular mortality (RR 0.83, 95% CI 0.69 to 1.01; NNTB 250; 3 studies, 21,870 participants; moderate certainty). There is probably little or no difference between apixaban and placebo in all-cause mortality (RR 1.09, 95% CI 0.88 to 1.35; number needed to treat for an additional harmful outcome (NNTH) 334; 2 studies, 8638 participants; moderate certainty) and cardiovascular mortality (RR 0.99, 95% CI 0.77 to 1.27; number needed to treat not applicable; 2 studies, 8638 participants; moderate certainty). Dabigatran may reduce the rate of all-cause mortality compared with placebo (RR 0.57, 95% CI 0.31 to 1.06; NNTB 63; 1 study, 1861 participants; low certainty). Dabigatran compared with placebo may have little or no effect on cardiovascular mortality, although the point estimate suggests benefit (RR 0.72, 95% CI 0.34 to 1.52; NNTB 143; 1 study, 1861 participants; low certainty). Two of the investigated NOACs were associated with an increased risk of major bleeding compared to placebo: apixaban (RR 2.41, 95% CI 1.44 to 4.06; NNTH 143; 2 studies, 8544 participants; high certainty) and rivaroxaban (RR 3.31, 95% CI 1.12 to 9.77; NNTH 125; 3 studies, 21,870 participants; high certainty). There may be little or no difference between dabigatran and placebo in the risk of major bleeding (RR 1.74, 95% CI 0.22 to 14.12; NNTH 500; 1 study, 1861 participants; low certainty). The results of the network meta-analysis were inconclusive between the different NOACs at all individual doses for all primary outcomes. However, low-certainty evidence suggests that apixaban (combined dose) may be less effective than rivaroxaban and dabigatran for preventing all-cause mortality after AMI in people without an indication for anticoagulation.
AUTHORS' CONCLUSIONS
Compared with placebo, rivaroxaban reduces all-cause mortality and probably reduces cardiovascular mortality after AMI in people without an indication for anticoagulation. Dabigatran may reduce the rate of all-cause mortality and may have little or no effect on cardiovascular mortality. There is probably no meaningful difference in the rate of all-cause mortality and cardiovascular mortality between apixaban and placebo. Moreover, we found no meaningful benefit in efficacy outcomes for specific therapy doses of any investigated NOACs following AMI in people without an indication for anticoagulation. Evidence from the included studies suggests that rivaroxaban and apixaban increase the risk of major bleeding compared with placebo. There may be little or no difference between dabigatran and placebo in the risk of major bleeding. Network meta-analysis did not show any superiority of one NOAC over another for our prespecified primary outcomes. Although the evidence suggests that NOACs reduce mortality, the effect size or impact is small; moreover, NOACs may increase major bleeding. Head-to-head trials, comparing NOACs against each other, are required to provide more solid evidence.
Topics: Humans; Dabigatran; Rivaroxaban; Network Meta-Analysis; Platelet Aggregation Inhibitors; Anticoagulants; Myocardial Infarction; Hemorrhage
PubMed: 38264795
DOI: 10.1002/14651858.CD014678.pub2 -
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 -
Polish Archives of Internal Medicine Oct 2023Despite availability of effective preventive therapies based on guidelines, patients with vascular diseases continue to be at a high risk for recurrent ischemic events.... (Review)
Review
Despite availability of effective preventive therapies based on guidelines, patients with vascular diseases continue to be at a high risk for recurrent ischemic events. Therefore, novel therapeutic strategies are required to further reduce the residual risk present in these patients. Platelet aggregation and fibrin organization are involved in arterial thrombosis. Rivaroxaban is capable of targeting both processes and has a synergistic effect when used in combination with acetylsalicylic acid (ASA), providing the so‑called dual pathway inhibition (DPI). The COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial showed that the DPI (a combination of rivaroxaban at 2.5 mg twice daily [vascular dose] and ASA at 100 mg once daily) reduced cardiovascular death, stroke, or myocardial infarction by 24% in patients with chronic coronary artery disease (CAD) and peripheral artery disease (PAD). Subsequently, the VOYAGER PAD (Vascular Outcomes Study of ASA Along with Rivaroxaban in Endovascular or Surgical Limb Revascularization for PAD) trial confirmed the effectiveness of the vascular dose of rivaroxaban in patients with PAD after lower‑extremity revascularization, as compared with ASA alone. Therefore, DPI is recommended in the patients with CAD (+/- PAD) or symptomatic PAD at a high risk of ischemia. The purpose of this review is to examine the clinical benefits and practical implications of DPI in the CAD and PAD patients.
Topics: Humans; Rivaroxaban; Cardiovascular Diseases; Platelet Aggregation Inhibitors; Outpatients; Factor Xa Inhibitors; Drug Therapy, Combination; Aspirin; Peripheral Arterial Disease; Ischemia
PubMed: 37738024
DOI: 10.20452/pamw.16566 -
Medicina (Kaunas, Lithuania) Aug 2023: Anticoagulants are a well-known risk factor for gastrointestinal bleeding (GIB). In recent years, direct oral anticoagulants (DOACs) have taken a leading role in the... (Observational Study)
Observational Study
: Anticoagulants are a well-known risk factor for gastrointestinal bleeding (GIB). In recent years, direct oral anticoagulants (DOACs) have taken a leading role in the treatment and prevention of thromboembolic incidents. The aim of this study was to investigate the prevalence of DOAC-treated patients with GIB whose plasma drug concentrations exceeded the cut-off values reported in the literature and to evaluate their clinical characteristics. : Patients who were admitted to the Intensive Care Unit in the period 2/2020-3/2022 due to GIB were prospectively included in the study and classified into three groups according to the prescribed type of DOAC (apixaban, rivaroxaban, and dabigatran). For all participants, it was determined if the measured plasma drug levels exceeded the maximum serum concentration (C or trough serum concentration (C) obtained from the available data. A comparison of clinical parameters between the patients with and without excess drug values was performed. Results: There were 90 patients (54.4% men) included in the study, of whom 27 were treated with dabigatran, 24 with apixaban, and 39 with rivaroxaban. According to C, there were 34 (37.8%), and according to C, there were 28 (31.1%) patients with excess plasma drug values. A statistically significant difference regarding excess plasma drug values was demonstrated between DOACs according to both C ( = 0.048) and C ( < 0.001), with the highest rate in the group treated with dabigatran (55.6% for C and 59.3% for C). Multivariate logistic regression showed that age (OR 1.177, = 0.049) is a significant positive and glomerular filtration rate (OR 0.909, = 0.016) is a negative predictive factor for excess plasma drug values. A total of six (6.7%) patients had fatal outcomes. : Plasma drug concentrations exceed cut-off values reported in the literature in more than one-third of patients with GIB taking DOAC, with the highest rate in the dabigatran group. Clinicians should be more judicious when prescribing dabigatran to the elderly and patients with renal failure. In these patients, dose adjustment, plasma drug monitoring, or substitution with other, more appropriate DOACs should be considered.
Topics: Aged; Male; Humans; Female; Dabigatran; Rivaroxaban; Plasma; Anticoagulants; Gastrointestinal Hemorrhage
PubMed: 37629757
DOI: 10.3390/medicina59081466 -
Medicine and Pharmacy Reports Oct 2023There is an increasing number of patients with cardiovascular diseases who require anticoagulant treatment to address the underlying disease. Types of anticoagulants... (Review)
Review
BACKGROUND AND AIMS
There is an increasing number of patients with cardiovascular diseases who require anticoagulant treatment to address the underlying disease. Types of anticoagulants include vitamin K antagonists, such as warfarin and coumarin derivatives, and also newer oral anticoagulants, including rivaroxaban, apixaban, edoxaban, and dabigatran. The use of these anticoagulants may impact the condition of patients undergoing oral surgery. If the treatment is discontinued, the patient may be at risk of thrombosis. On the other hand, if the treatment is continued, the patient may experience a postoperative bleeding episode, placing them at risk of both thrombosis and bleeding.
METHOD
The present article systematically reviews two different therapeutic regimens and their influence on hemorrhagic and thromboembolic events. The review included research from three databases and four specialized journals. The regimens examined were continuous versus discontinuous anticoagulant treatment and continuous versus interruption and switch to bridging therapy.
RESULTS
The most common surgical procedure examined in the review was tooth extraction, with a few studies also including soft tissue procedures. A total of seven eligible articles were identified, with five using the first treatment regimen of continuous versus discontinuous anticoagulant. These studies reported several cases of bleeding under continuous anticoagulant treatment during surgery. Two articles used the second treatment regimen of continuous versus interruption and switch to bridging therapy.
CONCLUSIONS
The results of both treatment categories (continuous versus discontinuous anticoagulant and continuous versus interruption and switch to bridging therapy) showed no significant differences in terms of bleeding events. However, the use of scores that assess the risk of thrombosis and bleeding can assist surgeons in anticipating the degree of postoperative complications and making informed treatment decisions.
PubMed: 37970201
DOI: 10.15386/mpr-2519 -
Cureus Nov 2023Cerebral venous thrombosis (CVT) is a rare cause of stroke which remains unsung among Bangladeshi physicians and the general population. Our objective was to provide a... (Review)
Review
Cerebral venous thrombosis (CVT) is a rare cause of stroke which remains unsung among Bangladeshi physicians and the general population. Our objective was to provide a comprehensive review of published data on Bangladeshi CVT patients. We searched all-electronic databases for Bangladeshi studies on CVT until November 2023, including literature in all languages. This study reviews the age of onset, gender distribution, radiological characteristics, and outcomes of Bangladeshi CVT patients. We included 13 studies (two observational and 11 case reports) that evaluated 102 CVT patients and found that women suffered CVT significantly higher than men (59.8% vs 40.2%; P =0.04), respectively. The overall age of the study population was 36.6±6.8, and men were significantly older than women (45.4±12.3 vs. 32.4±8.3; P<0.001). The most commonly affected sites were the superior sagittal sinus and transverse sinus thrombosis. Rivaroxaban was primarily used for long-term anticoagulation after initial low molecular weight heparin therapy. Furthermore, most studies observed an excellent clinical outcome with completed recanalisation on early follow-up angiography in three studies. In Bangladesh, women 1.5 times more commonly suffer from CVT and 13 years earlier than men. Although this review found that prompt diagnosis and anticoagulation therapy provides good clinical outcome, we recommended further studies to evaluate the long-term outcome, especially the safety and efficacy of oral anticoagulants, with recanalisation and recurrence rate.
PubMed: 38152776
DOI: 10.7759/cureus.49470 -
Thrombosis Research Dec 2023A high risk of gastrointestinal bleeding has been reported with the use of some direct oral anticoagulants (DOACs). This risk may be of particular concern in individuals...
INTRODUCTION
A high risk of gastrointestinal bleeding has been reported with the use of some direct oral anticoagulants (DOACs). This risk may be of particular concern in individuals with associated anaemia. The aim of this study is to investigate potential differences in the risks of gastrointestinal bleeding and stroke among the four available DOACs in patients with atrial fibrillation (AF) and moderate or severe anaemia.
MATERIALS AND METHODS
All Danish patients diagnosed with incident AF who had a baseline haemoglobin measurement and subsequently initiated DOAC therapy between 2012 and 2021 were identified through administrative registries. Only patients with moderate or severe anaemia (N = 7269) were included and evaluated regarding the risk of hospitalization for gastrointestinal bleeding and stroke. Standardized absolute 1-year risks of stroke and gastrointestinal bleeding were calculated from multivariable Cox regression analyses. DOACs were compared pairwise RESULTS: Compared with apixaban, both dabigatran and rivaroxaban were associated with a significantly increased risk of gastrointestinal bleeding with standardized 1-year risk ratios of 1.73 (95 % confidence interval [CI], 1.10-2.35) and 1.56 (95 % CI, 1.18-1.93), respectively, while no significant difference was seen in the comparison of apixaban with edoxaban 1.32 (95 % CI, 0.41-2.32). No significant differences in gastrointestinal bleeding were observed with pairwise comparisons of dabigatran, rivaroxaban and edoxaban. Finally, no significant difference in stroke risk among the four DOACs was observed.
CONCLUSION
In AF patients with moderate or severe anaemia, apixaban was associated with a significantly lower risk of gastrointestinal bleeding than dabigatran and rivaroxaban. No significant difference in stroke risk was observed across all four available DOACs.
Topics: Humans; Rivaroxaban; Atrial Fibrillation; Dabigatran; Anticoagulants; Gastrointestinal Hemorrhage; Stroke; Pyridones; Anemia; Administration, Oral
PubMed: 37939578
DOI: 10.1016/j.thromres.2023.10.013 -
The Oncologist Nov 2023Patients with gastrointestinal cancer (GICA) are at high risk for venous thromboembolism (VTE). Data from randomized clinical trials in cancer-associated VTE suggest...
BACKGROUND
Patients with gastrointestinal cancer (GICA) are at high risk for venous thromboembolism (VTE). Data from randomized clinical trials in cancer-associated VTE suggest that direct oral anticoagulants (DOACs) conferred similar or superior efficacy but a heterogeneous safety profile in patients with GICA. We compared the safety and effectiveness of DOACs in patients with GICA and VTE at MD Anderson Cancer Center.
MATERIALS AND METHODS
This was a retrospective chart review of patients with GICA and VTE receiving treatment with DOACs for a minimum of 6 months. Primary outcomes were the proportion of patients experiencing major bleeding (MB), clinically relevant non-major bleeding (CRNMB), and recurrent VTE. Secondary outcomes were time to bleeding and recurrent VTE.
RESULTS
A cohort of 433 patients with GICA who were prescribed apixaban (n = 300), or rivaroxaban (n = 133) were included. MB occurred in 3.7% (95% confidence interval [CI] 2.1-5.9), CRNMB in 5.3% (95% CI 3.4-7.9), and recurrent VTE in 7.4% (95% CI 5.1-10.3). The cumulative incidence rates of CRNMB and recurrent VTE were not significantly different when comparing apixaban to rivaroxaban.
CONCLUSION
Apixaban and rivaroxaban had a similar risk of recurrent VTE and bleeding and could be considered as anticoagulant options in selected patients with GICA and VTE.
Topics: Humans; Rivaroxaban; Venous Thromboembolism; Retrospective Studies; Neoplasm Recurrence, Local; Anticoagulants; Hemorrhage; Gastrointestinal Neoplasms; Administration, Oral
PubMed: 37310796
DOI: 10.1093/oncolo/oyad148 -
Journal of the American Heart... Apr 2024Concomitant atrial fibrillation and end-stage renal disease is common and associated with an unfavorable prognosis. Although oral anticoagulants have been well... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Concomitant atrial fibrillation and end-stage renal disease is common and associated with an unfavorable prognosis. Although oral anticoagulants have been well established to prevent thromboembolism, the applicability in patients under long-term dialysis remains debatable. The study aimed to determine the efficacy and safety of anticoagulation in the dialysis-dependent population.
METHODS AND RESULTS
An updated network meta-analysis based on MEDLINE, EMBASE, and the Cochrane Library was performed. Studies published up to December 2022 were included. Direct oral anticoagulants (DOACs, dabigatran, rivaroxaban, apixaban 2.5/5 mg twice daily), vitamin K antagonists (VKAs), and no anticoagulation were compared on safety and efficacy outcomes. The outcomes of interest were major bleeding, thromboembolism, and all-cause death. A total of 42 studies, including 3 randomized controlled trials, with 185 864 subjects were pooled. VKAs were associated with a significantly higher risk of major bleeding than either no anticoagulation (hazard ratio [HR], 1.47; 95% CI, 1.34-1.61) or DOACs (DOACs versus VKAs; HR, 0.74 [95% CI, 0.64-0.84]). For the prevention of thromboembolism, the efficacies of VKAs, DOACs, and no anticoagulation were equivalent. Nevertheless, dabigatran and rivaroxaban were associated with fewer embolic events. There were no differences in all-cause death with the administration of VKAs, DOACs, or no anticoagulation.
CONCLUSIONS
For dialysis-dependent populations, dabigatran and rivaroxaban were associated with better efficacy, while dabigatran and apixaban demonstrated better safety. No anticoagulation was a noninferior alterative, and VKAs were associated with the worst outcomes.
Topics: Humans; Atrial Fibrillation; Rivaroxaban; Dabigatran; Stroke; Network Meta-Analysis; Anticoagulants; Hemorrhage; Fibrinolytic Agents; Administration, Oral; Kidney Failure, Chronic; Thromboembolism; Randomized Controlled Trials as Topic
PubMed: 38606775
DOI: 10.1161/JAHA.123.034176