Dabigatran

Inhibition of Free Thrombin

Reduction of Fibrin Monomer Cross-linking

One of the primary functions of thrombin is to convert soluble fibrinogen into insoluble fibrin monomers. ahajournals.orgnih.gov These monomers then polymerize and are subsequently cross-linked by thrombin-activated Factor XIIIa, forming a stable fibrin clot. nih.govajnr.org this compound's inhibition of thrombin directly prevents the initial conversion of fibrinogen to fibrin. ahajournals.orgnih.gov Consequently, the formation of fibrin monomers and their subsequent cross-linking into a stable clot matrix is significantly reduced. ahajournals.orgtg.org.au

Influence on Platelet Activation Pathways

Thrombin is a potent activator of platelets, inducing their aggregation and the release of pro-coagulant substances. nih.govajnr.org It achieves this by cleaving protease-activated receptors (PARs) on the platelet surface. ahajournals.org this compound has been shown to inhibit thrombin-induced platelet aggregation in a dose-dependent manner. nih.govfrontiersin.org Studies have demonstrated that this compound effectively blocks platelet aggregation stimulated by thrombin, but does not affect aggregation induced by other agonists like arachidonic acid, collagen, or adenosine diphosphate (ADP). frontiersin.orgmdpi.com Research indicates that this compound can reduce the expression of platelet activation markers such as P-selectin and GPIIb/IIIa when stimulated by thrombin. nih.gov Interestingly, some studies suggest that while this compound inhibits thrombin-mediated platelet activation, it may also lead to an increased density of thrombin receptors on the platelet surface, which could potentially enhance platelet reactivity under certain conditions. mdpi.comthieme-connect.com Another novel mechanism suggests that this compound not only blocks the active site of thrombin but also inhibits its binding to platelets. researchgate.net

Role of Esterases in Prodrug Conversion

The biotransformation of this compound etexilate is not dependent on the cytochrome P450 enzyme system, a common pathway for drug metabolism. nih.govnih.gov Instead, the conversion is catalyzed by ubiquitous esterases, specifically carboxylesterases, found in various tissues including the gut, plasma, and liver. ahajournals.orgtga.gov.aunih.gov This hydrolysis begins in the intestine, meaning a mix of the prodrug and the active compound enters the portal vein. ahajournals.org

Research has identified two key carboxylesterases involved in this process: human carboxylesterase-1 (CES1) and human carboxylesterase-2 (CES2). nih.govresearchgate.netx-mol.net Studies suggest a sequential hydrolysis where intestinal CES2 first metabolizes this compound etexilate to an intermediate metabolite (M2), which is then hydrolyzed by CES1 in the liver to form the active this compound. nih.gov The efficient activity of CES2 is considered crucial for the formation of the active metabolite. researchgate.netx-mol.net

Factors Influencing Bioavailability

The absolute bioavailability of this compound after oral administration of this compound etexilate is relatively low, estimated to be around 6.5% to 7%. ahajournals.orgfda.govmedicinesinformation.co.nz Several factors can influence this.

One significant factor is the pH-dependent solubility of this compound etexilate mesylate, which has low solubility at a pH of 3 or higher. fda.gov This narrow range for sufficient dissolution is a likely contributor to its low bioavailability. fda.gov Co-administration with proton pump inhibitors, which increase gastric pH, has been shown to decrease this compound exposure. springermedizin.debioworld.commdpi.com

Furthermore, this compound etexilate is a substrate of the P-glycoprotein (P-gp) efflux transporter in the intestine. fda.govnih.govdovepress.com Co-administration with P-gp inhibitors can increase this compound's bioavailability. medsafe.govt.nznih.gov For instance, the timing of administration of a P-gp inhibitor like verapamil relative to this compound etexilate can significantly impact this compound exposure. nih.gov Conversely, P-gp inducers can decrease this compound exposure. medsafe.govt.nz

Plasma Concentration-Time Profiles

Following oral administration, this compound etexilate is rapidly absorbed, and peak plasma concentrations (Cmax) of the active this compound are typically reached within 0.5 to 2 hours in healthy volunteers. nih.govahajournals.orgeuropa.eu In postoperative patients, absorption may be slower on the day of surgery, with peak concentrations reached at around 6 hours. europa.eutg.org.au The plasma concentration-time profile is characterized by a rapid increase to Cmax followed by a biphasic decline. nih.gov The terminal half-life of this compound is approximately 8 hours after a single dose and extends to 12 to 17 hours after multiple doses. ahajournals.orgnih.gov

Achievement of Steady-State Concentrations

Steady-state concentrations of this compound are generally achieved within 2 to 3 days of multiple-dose administration. ahajournals.orgbioworld.commedicinesinformation.co.nz Studies have shown no unexpected accumulation of the drug with repeated dosing. nih.govahajournals.org At steady state, plasma concentrations fluctuate between a peak (Cmax) and a trough (Cmin) level before the next dose. For instance, in patients with atrial fibrillation taking 150 mg twice daily, peak concentrations are around 180 ng/mL and trough concentrations are about 90 ng/mL. ahajournals.orgoup.com

Inter-individual and Intra-individual Variability in Exposure

Despite its predictable pharmacokinetics, there is notable variability in this compound exposure among and within individuals. frontiersin.orgresearchgate.netscispace.com The inter-individual coefficient of variation for this compound plasma concentrations in patients has been reported to be in the range of 51% to 64%. frontiersin.orgresearchgate.net Intra-individual variability is lower, with a coefficient of variation between 32% and 40%. frontiersin.orgresearchgate.net In healthy volunteers, the inter-subject variability in pharmacokinetics is around 30%. frontiersin.org

This variability can be influenced by several factors, including genetic polymorphisms in genes encoding for the P-glycoprotein transporter (ABCB1) and carboxylesterase 1 (CES1). frontiersin.orgahajournals.orgrpcardio.online For example, certain genetic variants in the CES1 gene have been associated with lower this compound plasma concentrations. ahajournals.orgumich.edu Age and gender can also contribute to pharmacokinetic differences, largely due to variations in renal function. nih.govtandfonline.com

Renal Clearance Mechanisms

Renal excretion is the predominant elimination route for this compound, accounting for approximately 80% of its total clearance after intravenous administration. ahajournals.orgahajournals.orgnih.gov Following oral administration of its prodrug, this compound etexilate, about 7% of the drug's radioactivity is recovered in the urine and 86% in the feces. drugbank.comfda.gov The significant renal clearance means that the drug's exposure increases as renal function declines. fda.gov Studies have shown that in cases of end-stage renal failure, hemodialysis can effectively remove this compound from the plasma, with a mean removal of 62% at 2 hours and 68% at 4 hours. ahajournals.org

The half-life of this compound is approximately 12 to 17 hours in individuals with healthy renal function. drugbank.comfda.gov However, this can be significantly prolonged in patients with renal impairment. Research in patients with severe chronic kidney disease (creatinine clearance of 15 to 30 ml/min) showed a terminal half-life at a steady state of 27.8 hours. jacc.org

Table 1: Impact of Renal Impairment on this compound Pharmacokinetics

Contribution of P-glycoprotein Efflux Transporter

The prodrug, this compound etexilate, is a substrate for the P-glycoprotein (P-gp) efflux transporter, which is located in the small intestine. acc.orgtg.org.au This transporter pumps the drug back into the intestinal lumen, thereby limiting its oral bioavailability. acc.orgtg.org.au However, the active form, this compound, is not a substrate for P-gp. acc.orgnih.gov

Hepatic Elimination Considerations

While renal clearance is the primary route of elimination, a smaller portion of this compound is handled by the liver. Approximately 20% of this compound undergoes hepatic elimination. ahajournals.orgnih.govannalsgastro.gr This process involves conjugation with glucuronic acid to form active metabolites known as acyl glucuronides. ahajournals.orgnih.gov These metabolites, which include four positional isomers (1-O, 2-O, 3-O, and 4-O-acylglucuronides), exhibit pharmacological activity similar to the parent compound. drugbank.comnih.gov

The formation of these metabolites is catalyzed by UDP-glucuronosyltransferases (UGTs), with UGT1A9, UGT2B7, and UGT2B15 being involved. nih.gov Research suggests that UGT2B15 is the major contributor to this process. nih.govfrontiersin.org Studies in patients with mild to moderate hepatic impairment have shown that the pharmacokinetics of this compound are not significantly altered. annalsgastro.grnih.gov

Activated Partial Thromboplastin Time (aPTT) Correlation Research

The activated partial thromboplastin time (aPTT) is prolonged by this compound. fda.gov However, the relationship between this compound concentration and aPTT is not always linear, especially at higher drug levels. nih.govdroracle.ai Research has shown a modest correlation (r=0.80) between this compound levels and aPTT, but this correlation weakens at supratherapeutic concentrations. nih.gov

Different aPTT reagents exhibit varying responsiveness to this compound, which means that therapeutic ranges need to be established by individual laboratories for their specific reagents. nih.govdroracle.ai For example, one study found that the aPTT ranges corresponding to therapeutic this compound levels (90-180 ng/ml) were different across four different reagents. nih.gov The active metabolites of this compound, the acylglucuronides, have been shown to prolong the aPTT to a similar extent as the parent compound. nih.govresearchgate.net

Ecarin Clotting Time (ECT) Assessment and Sensitivity

The Ecarin Clotting Time (ECT) is a laboratory test that is highly sensitive to the effects of direct thrombin inhibitors like this compound. practical-haemostasis.comtaylorandfrancis.com ECT measures the time it takes for ecarin, a component of snake venom, to convert prothrombin to meizothrombin, a process that is inhibited by this compound. practical-haemostasis.com

Research has demonstrated a linear and dose-dependent relationship between this compound concentrations and ECT. practical-haemostasis.com One study reported a moderate correlation (r = 0.80) between trough plasma this compound concentration and clotting time in the ClotPro ecarin clotting assay. nih.gov Unlike aPTT, the ECT is generally considered a more reliable and specific measure of this compound's anticoagulant activity. oup.com However, ECT can be factitiously elevated in patients with low levels of fibrinogen or prothrombin. researchgate.net

Thrombin Time (TT) Assay Responses

The Thrombin Time (TT) assay is highly sensitive to the anticoagulant effects of this compound. oup.comnih.gov Research indicates a direct and linear correlation between the plasma concentration of this compound and the prolongation of TT. oup.compractical-haemostasis.comtga.gov.au This sensitivity, however, can be a limitation for quantitative monitoring at therapeutic drug concentrations, as the TT can become excessively prolonged, often exceeding the measurable limits of laboratory coagulometers. practical-haemostasis.comopenaccessjournals.comacc.org For instance, conventional TT assays can show more than a 10-fold prolongation at peak this compound levels. practical-haemostasis.com

Despite its limitations for precise quantification, the TT assay serves a critical qualitative role. openaccessjournals.com A normal TT result is considered a reliable indicator for excluding the presence of clinically significant levels of this compound. practical-haemostasis.comopenaccessjournals.comashpublications.org Conversely, a prolonged TT confirms the presence of a direct thrombin inhibitor like this compound in the plasma sample. bloodworksnw.org

To overcome the over-sensitivity of standard TT assays, modified versions have been developed. The dilute Thrombin Time (dTT) and the Hemoclot® Thrombin Inhibitor assay, which is a type of dTT, show a linear correlation with this compound levels over a broad and clinically relevant range, making them suitable for quantitative assessment. tga.gov.aunih.gov Research has demonstrated that a plasma-diluted thrombin time assay provides a linear dose-response curve, allowing for the measurement of this compound concentrations. oup.com The sensitivity of various TT reagents can differ based on their thrombin concentration, affecting the results. nih.gov For example, one study found that a reagent with a lower thrombin concentration was more sensitive and became unmeasurable at lower this compound concentrations compared to reagents with higher thrombin concentrations. nih.gov

Prothrombin Time (PT) and International Normalized Ratio (INR) Insensitivity

The Prothrombin Time (PT) and the derived International Normalized Ratio (INR) are largely insensitive to the anticoagulant activity of this compound at therapeutic concentrations. openaccessjournals.comboehringer-ingelheim.comahajournals.orgahdbonline.com Consequently, these tests are not recommended or reliable for monitoring the effect of this compound. tga.gov.auashpublications.orgahajournals.orgdroracle.ai The INR, which is standardized for monitoring Vitamin K antagonists like warfarin, does not accurately reflect the anticoagulant effect of direct oral anticoagulants (DOACs) and cannot be interpreted in the same manner. acc.orgboehringer-ingelheim.comdroracle.ai

Studies have consistently shown a poor correlation between this compound plasma concentrations and PT/INR values. bloodworksnw.orgnih.gov While very high, supratherapeutic concentrations of this compound may lead to a prolongation of the PT and an elevation in the INR, these changes are not proportional to the drug level within the therapeutic range. openaccessjournals.comahdbonline.com In a cross-sectional pharmacodynamic study, 29% of patient samples with therapeutic this compound levels showed a normal PT. nih.gov Therefore, relying on PT/INR for assessing this compound's anticoagulant effect is inappropriate and can be misleading. ahdbonline.com

P-glycoprotein Inhibitor Interactions and Their Impact on Exposure

Co-administration of this compound etexilate with drugs that are strong inhibitors of P-glycoprotein can lead to increased absorption and consequently higher plasma concentrations and exposure to this compound. uw.edutg.org.au This increased exposure can enhance the anticoagulant effect.

Research has investigated the effects of several P-gp inhibitors:

Ketoconazole: A potent P-gp inhibitor, ketoconazole significantly increases this compound exposure. tg.org.auahajournals.org

Verapamil: Co-administration with verapamil, a moderate P-gp inhibitor, also increases this compound plasma concentrations. tg.org.auahajournals.org The extent of this interaction is dependent on the timing of administration. The greatest increase in this compound exposure occurs when immediate-release verapamil is given one hour before this compound, resulting in a 2.4-fold increase in the area under the curve (AUC). ahajournals.org If verapamil is administered two hours after this compound, the interaction is negligible. ahajournals.org Physiologically based pharmacokinetic (PBPK) modeling suggests that for patients with mild or moderate renal impairment, a dose reduction of this compound may be necessary when co-administered with verapamil. hiv-druginteractions.orgnih.gov

Amiodarone: This P-gp inhibitor can increase this compound plasma levels. ahajournals.orgacc.org

Quinidine: Co-administration with quinidine, a strong P-gp inhibitor, can also elevate this compound concentrations. ahajournals.org

Clarithromycin: As a P-gp inhibitor, clarithromycin may increase this compound concentrations. tg.org.au

Dronedarone: This moderate P-gp inhibitor significantly elevates this compound levels, particularly in patients with renal impairment. acc.org

Ritonavir: Studies on the interaction with ritonavir, which has mixed P-gp induction and inhibition effects, showed no significant change in this compound pharmacokinetics when administered simultaneously. hiv-druginteractions.org However, when this compound was given two hours before ritonavir, its AUC and Cmax decreased by 29% and 27%, respectively. hiv-druginteractions.org

P-glycoprotein Inducer Interactions

Conversely, co-administration with potent inducers of P-glycoprotein can decrease the absorption and plasma exposure of this compound, potentially reducing its anticoagulant efficacy. uw.edutg.org.au

Rifampicin: A strong P-gp inducer, rifampicin has been shown to significantly reduce this compound exposure. ahajournals.orgahajournals.org One study reported that a 6-day course of rifampin decreased the total AUC of this compound by 66%. ahajournals.org This inducing effect was observed to diminish seven days after discontinuing rifampicin. medsafe.govt.nz

Interactions with Cytochrome P450 Enzymes (Absence of)

This compound is not metabolized by the cytochrome P450 (CYP450) enzyme system. bloodworksnw.orgahajournals.orgsps.nhs.uknih.govaafp.org This characteristic means that this compound has a low potential for drug-drug interactions mediated by CYP450 enzymes. ahajournals.orgnih.gov Unlike many other medications, its pharmacokinetics are not affected by inhibitors or inducers of CYP enzymes such as CYP3A4. acc.orgahajournals.orgnih.gov However, a recent in vitro study using a microdose of this compound etexilate suggested a potential role for CYP3A-mediated metabolism, indicating the complexity of its metabolic pathways at different dose levels. frontiersin.orgresearchgate.net

Co-administration Effects with Other Therapeutic Agents (e.g., antiplatelets, proton pump inhibitors)

Antiplatelet Agents: The concomitant use of antiplatelet agents such as acetylsalicylic acid (ASA) and clopidogrel with this compound does not significantly alter the pharmacokinetics of this compound. medsafe.govt.nzeuropa.eu However, from a pharmacodynamic perspective, this combination can increase the risk of bleeding compared to either agent alone. ahajournals.orgmedsafe.govt.nzeuropa.eu In a large clinical trial, the co-administration of ASA or clopidogrel with this compound was associated with a higher rate of major bleeding events. medsafe.govt.nz

Proton Pump Inhibitors (PPIs): The absorption of this compound etexilate is facilitated by an acidic environment. ahajournals.org Co-administration with PPIs, such as pantoprazole, which raise gastric pH, can lead to a slight reduction in this compound exposure. ahajournals.orgnih.govoup.com Studies have shown that pantoprazole co-administration decreased the this compound area under the plasma concentration-time curve by approximately 30%. medsafe.govt.nz However, in large clinical trials, this modest reduction in bioavailability was not found to be clinically relevant, with no significant impact on efficacy or bleeding outcomes. ahajournals.orgmedsafe.govt.nzoup.com Population pharmacokinetic analyses have also concluded that the changes in this compound exposure caused by PPIs are not clinically significant. medsafe.govt.nz

Carboxylesterase 1 (CES1) Gene Variants (e.g., rs2244613, rs8192935)

The conversion of the prodrug this compound etexilate to its active form, this compound, is a critical step primarily mediated by the enzyme carboxylesterase 1 (CES1), which is encoded by the CES1 gene. frontiersin.orgahajournals.org Genetic variations in CES1 can influence the rate of this conversion, leading to altered plasma concentrations of the active drug. frontiersin.org

rs2244613 : This single nucleotide polymorphism (SNP) located in the CES1 gene is significantly associated with this compound's trough concentrations. ahajournals.org The minor allele of rs2244613 is linked to reduced trough levels of this compound. ahajournals.orgnih.gov Specifically, each minor allele has been associated with a 15% decrease in trough concentrations. ahajournals.orgnih.gov This is thought to be because the variant affects the hydrolysis of this compound etexilate. ahajournals.org

rs8192935 : This CES1 variant has been primarily associated with this compound's peak plasma concentrations. ahajournals.orgdovepress.com Studies have shown that each minor allele of rs8192935 can lead to a 12% decrease in adjusted peak concentrations. ahajournals.org However, its effect on trough levels has also been noted, with some research indicating that the T allele is associated with lower drug concentrations compared to the CC genotype. mdpi.com The influence of rs8192935 on this compound levels might also be due to its linkage with other functional variants. mdpi.commdpi.com

ATP Binding Cassette Subfamily B Member 1 (ABCB1/MDR1) Gene Variants (e.g., rs1128503, rs2032582, rs1045642, rs4148738)

The bioavailability of this compound etexilate is heavily influenced by the P-glycoprotein (P-gp) efflux transporter, which is encoded by the ABCB1 (also known as MDR1) gene. mdpi.comnih.gov This transporter is located in the intestines and pumps the prodrug back into the gut lumen, reducing the amount absorbed into the bloodstream. ahajournals.orgahajournals.org Variants in the ABCB1 gene can alter P-gp activity and, consequently, this compound exposure. mdpi.commdpi.com

rs1045642 (c.3435C>T) : This well-studied variant has been linked to this compound peak concentrations. mdpi.com The TT genotype, in particular, has been associated with significantly higher peak plasma levels of this compound compared to the CC genotype. mdpi.comdovepress.comnih.gov This SNP is in linkage disequilibrium with rs4148738. ahajournals.org

rs1128503 (c.1236C>T) and rs2032582 (c.2677G>T/A) : These two SNPs, along with rs1045642, often occur together as a haplotype. mdpi.commdpi.com While some studies have investigated their combined effect, their individual and collective impact on this compound pharmacokinetics remains an area of active research, with some reports showing no significant association when analyzed as a haplotype. mdpi.comdovepress.comnih.gov

UGT2B15 Gene as a Potential Candidate

Beyond activation and transport, the elimination of active this compound involves metabolism, specifically glucuronidation. rpcardio.onlinemdpi.com The enzyme Uridine 5'-diphospho-glucuronosyltransferase 2B15, encoded by the UGT2B15 gene, is the primary isoform responsible for converting this compound into its acylglucuronide metabolite. mdpi.commdpi.comresearchgate.net Genetic variants in UGT2B15, such as the UGT2B152* polymorphism (rs1902023), are known to affect the glucuronidation of other drugs and are considered an important predictor of inter-individual variability in drug clearance. mdpi.commdpi.com Therefore, the UGT2B15 gene is a potential candidate for influencing this compound's safety and efficacy profile by altering its rate of elimination. rpcardio.onlinemdpi.com

Association of Gene Variants with Peak and Trough Concentrations

Different genetic variants are associated with either the maximum (peak) or minimum (trough) drug concentrations during a dosing interval. A genome-wide association study identified that the CES1 SNP rs2244613 was primarily associated with trough concentrations, while the ABCB1 SNP rs4148738 and the CES1 SNP rs8192935 were associated with peak concentrations. ahajournals.orgahajournals.org

The table below summarizes findings on the association between specific genotypes and this compound plasma concentrations from various research studies.

Influence of Genetic Factors on Bleeding Risk

The genetically determined variability in this compound concentrations has a direct impact on clinical safety, particularly the risk of bleeding. Higher drug exposure can increase anticoagulant intensity and elevate the risk of hemorrhagic complications, while lower exposure might compromise efficacy.

The CES1 SNP rs2244613 has the most clearly defined relationship with bleeding risk. ahajournals.orgahajournals.org Carriage of the minor allele of rs2244613, which is associated with lower trough concentrations, is also linked to a significantly lower risk of bleeding in patients treated with this compound. ahajournals.orgahajournals.orgnih.gov

The table below details the reported influence of genetic variants on bleeding outcomes.

In contrast, the variants primarily associated with peak concentrations, CES1 rs8192935 and ABCB1 rs4148738, have not been consistently associated with the risk of bleeding or ischemic events. ahajournals.orgahajournals.orgnih.gov

Need for Replicated Studies in Diverse Populations

To ensure the broad applicability and accuracy of pharmacogenomic algorithms, it is imperative to conduct replicated studies in diverse populations. tandfonline.com The frequency of genetic variants can differ significantly across various ethnic groups, which can influence the predictive power of a dosing algorithm developed in one population when applied to another. tandfonline.com For instance, the frequency of the C allele of the CES1 single-nucleotide polymorphism (SNP) rs2244613, which is associated with lower this compound concentrations, varies from 15% in Europeans to 60% in Asians. ahajournals.org

This highlights the necessity for ethnic-specific algorithms or algorithms that have been validated across multiple ethnicities. tandfonline.com Most pharmacogenomic studies on this compound have been conducted in populations of European or Asian descent, creating a gap in our understanding of its pharmacogenomics in other groups, such as individuals of African descent. nih.gov Failing to include diverse populations in research can lead to health disparities, as the benefits of personalized medicine may not extend to all patients. nih.gov Therefore, international collaborations and consortia are crucial for pooling data and resources to validate findings across a wide spectrum of populations. nih.gov Studies in healthy subjects from different ethnicities, like the Chinese population, have already shown different pharmacokinetic profiles compared to Caucasians, suggesting that genetic differences may contribute to these variations. frontiersin.orgdovepress.com

Genome-Wide Association Studies (GWAS) Findings

Genome-wide association studies (GWAS) have been instrumental in identifying genetic loci associated with this compound's pharmacokinetics and clinical outcomes without prior hypotheses about specific genes. nih.gov A landmark GWAS conducted within the Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) trial provided significant insights into the genetic determinants of this compound response. ahajournals.orgnih.gov

This study, involving 2,944 participants of European ancestry, identified several key single-nucleotide polymorphisms (SNPs). ahajournals.orgnih.gov

The CES1 gene encodes carboxylesterase 1, an enzyme responsible for converting the prodrug this compound etexilate into its active form, this compound. mdpi.comahajournals.org The ABCB1 gene encodes the P-glycoprotein transporter, which is involved in the intestinal efflux of this compound etexilate. ahajournals.orgfrontiersin.org The findings from the RE-LY GWAS underscore the critical role of these two genes in this compound's metabolism and disposition. ahajournals.org

The minor allele of CES1 rs2244613, present in 32.8% of the RE-LY participants, was associated not only with lower this compound exposure but also with a clinically relevant outcome: a lower risk of bleeding. ahajournals.orgnih.gov Interestingly, this association with bleeding was not observed in patients treated with warfarin, and there was a significant interaction between treatment and carrier status. ahajournals.orgnih.gov

While the RE-LY study was a pivotal GWAS for this compound, it is important to note that the field of pharmacogenomics for direct oral anticoagulants (DOACs) is still emerging. tandfonline.comnih.gov Few other large-scale GWAS for DOACs have been published. tandfonline.comspringermedizin.de A more recent GWAS did not find significant associations with bleeding for rivaroxaban or apixaban but did identify a potential signal in the BAIAP2L2 gene associated with bleeding across different DOACs, though this requires replication. springermedizin.de

Further research, including focused studies on the CES1 gene and its numerous polymorphisms, is warranted to uncover additional genetic variants that may influence this compound's metabolism and clinical outcomes. mdpi.com

Propensity Score Matching and Adjustment Methodologies

Venous Thromboembolism (VTE) Treatment and Prevention

The efficacy of this compound in the treatment and prevention of venous thromboembolism (VTE) has been evaluated in a series of key clinical trials. The RE-COVER and RE-COVER II trials were designed to assess this compound's role in treating acute VTE. dovepress.comahajournals.org In these studies, patients with acute VTE were initially treated with a parenteral anticoagulant before being randomized to either this compound or warfarin. ahajournals.org The pooled analysis of these two trials demonstrated that this compound was non-inferior to warfarin in preventing recurrent VTE or VTE-related death. ahajournals.org The primary outcome occurred in 2.4% of patients in the this compound group compared to 2.1% in the warfarin group in the RE-COVER trial, and 2.3% versus 2.2% in the RE-COVER II trial. dovepress.comahajournals.org

For the extended treatment and secondary prevention of VTE, the RE-MEDY and RE-SONATE trials provide significant insights. nice.org.uk The RE-MEDY trial compared this compound to warfarin for long-term secondary prevention in patients who had already completed 3 to 12 months of anticoagulant therapy. dovepress.comclinicaltrials.gov this compound was found to be non-inferior to warfarin for preventing recurrent VTE. dovepress.com The RE-SONATE trial evaluated this compound against a placebo for extended VTE prevention in patients who had completed 6 to 18 months of initial therapy. nice.org.ukacc.org Results showed that this compound was superior to placebo, demonstrating a 92% reduction in the risk of recurrent symptomatic VTE. dovepress.com The primary outcome of recurrent VTE occurred in 0.4% of the this compound group versus 5.6% of the placebo group. acc.org

Interactive Data Table: Efficacy of this compound in VTE Treatment and Prevention

Secondary Prevention Strategies

This compound has been investigated for secondary prevention in various contexts beyond VTE. A significant area of research is in secondary stroke prevention for patients with embolic stroke of undetermined source (ESUS). The RE-SPECT ESUS trial was a large-scale study that randomized approximately 6,000 patients with recent ESUS to either this compound or acetylsalicylic acid (ASA). clinicaltrials.gov The trial aimed to determine if this compound was more effective than ASA in preventing recurrent stroke in this specific patient population. clinicaltrials.gov

In the context of VTE, the RE-MEDY and RE-SONATE trials serve as pivotal studies for secondary prevention strategies. clinicaltrials.gov RE-MEDY established this compound's non-inferiority to warfarin for long-term prevention, while RE-SONATE confirmed its superiority over placebo for extended prevention. dovepress.comnice.org.uk Research has also extended into pediatric populations. An open-label, phase 3 trial (NCT02197416) evaluated this compound for the secondary prevention of VTE in children with persistent risk factors, demonstrating a favorable safety profile. uzh.chnih.gov In this study, no children with congenital heart disease experienced major bleeding events, and the rate of recurrent VTE was low. nih.gov

Evaluation in Specific Clinical Scenarios (e.g., post-orthopedic surgery, acute coronary syndrome)

Post-Orthopedic Surgery

This compound has been extensively studied for VTE prophylaxis in patients undergoing major orthopedic surgeries, such as total hip arthroplasty (THA) and total knee arthroplasty (TKA). ijoro.org A series of phase III trials, including RE-NOVATE (THA), RE-NOVATE II (THA), RE-MODEL (TKA), and RE-MOBILIZE (TKA), compared this compound with the low-molecular-weight heparin (LMWH) enoxaparin. ecrjournal.comresearchgate.net In the RE-NOVATE and RE-MODEL trials, this compound demonstrated non-inferiority to enoxaparin for the composite endpoint of total VTE and all-cause mortality. ecrjournal.com The RE-NOVATE II trial also confirmed that oral this compound was as effective as enoxaparin for thromboprophylaxis after primary total hip arthroplasty. ijoro.org These studies collectively support this compound as a viable oral option for VTE prevention in this high-risk surgical setting. ijoro.orgmedscape.com

Interactive Data Table: this compound in VTE Prophylaxis Post-Orthopedic Surgery | Trial | Surgery Type | Comparison | Primary Efficacy Endpoint (Total VTE and All-Cause Mortality) | |---|---|---|---| | | | | This compound | Enoxaparin | | RE-NOVATE | THA | this compound vs. Enoxaparin | 6.0% | 6.7% | | RE-NOVATE II | THA | this compound vs. Enoxaparin | 7.7% | 8.8% | | RE-MODEL | TKA | this compound vs. Enoxaparin | 36.4% | 40.5% | | RE-MOBILIZE | TKA | this compound vs. Enoxaparin | 31.1% | 25.3% | Data sourced from reviews of the respective clinical trials. ecrjournal.com

Acute Coronary Syndrome (ACS)

The role of this compound in patients with acute coronary syndrome (ACS) has been explored, particularly as an adjunct to standard dual antiplatelet therapy (aspirin and clopidogrel). nih.gov The RE-DEEM trial was a phase II, double-blind, placebo-controlled study that evaluated four different doses of this compound in patients with a recent myocardial infarction. acc.orgoup.com The primary outcome was a composite of major or clinically relevant minor bleeding over six months. nih.gov The trial found a dose-dependent increase in bleeding events with this compound compared to placebo when added to dual antiplatelet therapy. nih.govoup.com Regarding efficacy indicators, while this compound reduced coagulation activity, there was no significant difference in the composite of cardiovascular death, myocardial infarction, or stroke between the this compound groups and the placebo group. nih.gov A subsequent meta-analysis of seven trials, including RE-DEEM, suggested that this compound was associated with a significantly higher risk of myocardial infarction or ACS compared to control treatments (warfarin, enoxaparin, or placebo). nih.gov

Interactive Data Table: RE-DEEM Trial Outcomes in ACS (6-Month Follow-up)

Data sourced from the RE-DEEM trial publication. nih.govoup.com

Major Bleeding Events (e.g., intracranial hemorrhage, gastrointestinal hemorrhage)

Specifically for ICH, multiple studies and meta-analyses have consistently shown a reduced risk with this compound compared to warfarin. nih.govnih.gov In a large real-world study of Medicare beneficiaries, the risk of ICH was significantly lower in patients taking this compound. nih.gov Conversely, the risk of major GI bleeding is often reported to be higher with this compound than with warfarin. boehringer-ingelheim.comuic.eduaafp.org The RE-LY trial reported a higher rate of GI bleeds with the 150 mg dose of this compound compared to warfarin. boehringer-ingelheim.com However, in an Asian population study, this compound was not found to increase the risk of major GI bleeding compared to warfarin. ahajournals.org

In the context of VTE treatment, the pooled analysis of RE-COVER and RE-COVER II showed that major bleeding occurred in 1.4% of this compound patients versus 2.2% of warfarin patients, a difference that was not statistically significant. ahajournals.org In ACS patients in the RE-DEEM trial, major bleeding increased in a dose-dependent manner with this compound. nih.gov

Interactive Data Table: Major Bleeding Events with this compound vs. Warfarin (RE-LY Trial)

Data sourced from the RE-LY trial. Note: Some sources report slightly different event rates based on analysis populations. tga.gov.au

Mortality Rates and Causes

The effect of this compound on mortality has been a key outcome in clinical trials and subsequent analyses. A meta-analysis of 14 RCTs found that this compound was associated with a statistically significant reduction in all-cause mortality compared with comparators (Peto odds ratio 0.89). ahajournals.org Another meta-analysis of three trials showed a trend toward lower mortality with this compound, although it did not reach statistical significance (Relative Risk 0.88). nih.gov

In a large real-world study of an Asian population with nonvalvular atrial fibrillation, this compound was associated with a significantly reduced risk of all-cause mortality compared with warfarin (Hazard Ratio 0.45). ahajournals.org Similarly, a study of elderly Medicare patients in the US found that this compound was associated with lower all-cause mortality compared to warfarin. aafp.org In the RE-LY trial, mortality rates were slightly lower in both this compound arms compared to the warfarin arm. ahajournals.org An analysis of hospitalizations in the RE-LY trial did not find significant differences in mortality risk following hospitalization between the treatment groups. oup.com Deaths from bleeding events are an important component of safety assessment. An analysis of five phase III studies found a trend toward decreased mortality within 30 days of a major bleeding event with this compound compared to warfarin. researchgate.net

Interactive Data Table: All-Cause Mortality in Major Studies

Data sourced from respective publications. ahajournals.orgnih.govaafp.orgahajournals.org

Myocardial Infarction Incidence in Comparative Studies

The potential for an increased risk of myocardial infarction (MI) with this compound has been a subject of extensive investigation, primarily arising from observations in key clinical trials comparing it with warfarin.

The landmark Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY) trial, which assessed two doses of this compound against warfarin for stroke prevention in atrial fibrillation, noted a numerical, albeit not always statistically significant, increase in MI events with this compound. ahajournals.orgacc.org In the RE-LY trial, the annual rates of MI were 0.82% for this compound 110 mg twice daily and 0.81% for this compound 150 mg twice daily, compared to 0.64% for warfarin. ahajournals.org The hazard ratios (HR) versus warfarin were 1.29 (95% CI 0.96–1.75) for the 110 mg dose and 1.27 (95% CI 0.94–1.71) for the 150 mg dose, neither of which reached statistical significance. ahajournals.org

A comprehensive analysis of pooled data from 14 comparative trials involving 42,484 patients across five different indications also examined this issue. nih.govresearchgate.net When comparing this compound to warfarin in patients with atrial fibrillation and for venous thromboembolism treatment, the odds ratio (OR) for MI was 1.30 (95% CI 0.96-1.76) for this compound 110 mg and 1.42 (95% CI 1.07-1.88) for this compound 150 mg, suggesting a more protective effect of well-controlled warfarin. nih.govresearchgate.net However, when compared with enoxaparin or a placebo, this compound showed similar rates of MI. nih.govresearchgate.net

Meta-analyses have also contributed to the discussion. One meta-analysis of seven non-inferiority randomized controlled trials indicated a significant 33% increase in the risk of MI with this compound, corresponding to an absolute risk increase of 0.27% during follow-up. ahajournals.org Another comparative analysis suggested that this compound was associated with an increased risk of MI compared to vitamin K antagonists (VKA), apixaban, and rivaroxaban. ecrjournal.com

Conversely, some "real-world" observational studies have presented contrasting findings. A nationwide cohort study in Denmark found that treatment with this compound was associated with a lower incidence of MI compared to warfarin. jacc.org This highlights the potential discrepancies between the controlled environment of clinical trials and everyday clinical practice.

It has been suggested that the observed difference in MI rates may not be due to a harmful effect of this compound but rather a beneficial, protective effect of warfarin. fda.gov The RE-LY trial had low statistical power to detect a definitive difference in MI, an outcome that was less frequent than stroke. ahajournals.org

To provide a broader perspective on myocardial ischemic events, a composite outcome including MI, unstable angina, cardiac arrest, and cardiac death was analyzed in the RE-LY trial. The annual rates for this composite outcome were 3.16% for this compound 110 mg, 3.33% for this compound 150 mg, and 3.41% for warfarin, with no statistically significant differences observed. ahajournals.org

Incidence of Myocardial Infarction in the RE-LY Trial

Data sourced from Circulation. ahajournals.org

Risk Stratification Models for Bleeding

The use of anticoagulants inherently carries a risk of bleeding. To help clinicians assess and manage this risk, several risk stratification models have been developed and validated in patients with atrial fibrillation, including those treated with this compound and other direct oral anticoagulants (DOACs).

Historically, bleeding risk scores were primarily developed and validated for patients on warfarin. ahajournals.org The HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol concomitantly) score is one of the most widely used. ahajournals.orgpractical-haemostasis.com Studies have shown that in patients with venous thromboembolism, a one-point increase in the HAS-BLED score is associated with a 20% to 30% increase in the bleeding rate. nih.gov

However, the predictive value of these warfarin-era scores for patients on DOACs has been a subject of investigation. Research indicates that scores like HAS-BLED, ORBIT (Older age, Reduced hemoglobin/hematocrit/history of anemia, Bleeding history, Insufficient kidney function, and Treatment with antiplatelet), and ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) have shown modest predictive value for bleeding in patients taking this compound, apixaban, rivaroxaban, or edoxaban. ahajournals.org

A comparative analysis within the RE-LY trial population found that the ORBIT score demonstrated the best discrimination and calibration for predicting major, life-threatening, and intracranial bleeding compared to HAS-BLED, ATRIA, and HEMORR₂HAGES . nih.gov The c-indices for the ORBIT score were significantly better than for the HAS-BLED score for these outcomes. nih.gov

More recently, risk scores specifically developed for patients on DOACs have emerged. The DOAC Score was developed using data from the this compound arm of the RE-LY trial and further refined using the GARFIELD-AF registry. ahajournals.orgpractical-haemostasis.com This score incorporates factors such as age and creatinine clearance. ahajournals.org In validation studies, the DOAC Score showed better predictive performance for major bleeding compared to the HAS-BLED score in cohorts of patients on various DOACs. nih.gov

Another model, the VTE-BLEED score, was developed from the RE-COVER studies to predict major bleeding in patients with venous thromboembolism on stable anticoagulation. ersnet.org This score accurately predicted major bleeding events after the first 30 days of treatment in patients on both this compound and warfarin. ersnet.org

The performance of these scores can vary depending on the patient population and the specific bleeding outcome being assessed. For instance, in a retrospective study of patients starting DOACs, HAS-BLED, ATRIA, and ORBIT showed moderate and similar discriminatory ability for major bleeding. revespcardiol.org

Comparison of Bleeding Risk Scores in the RE-LY Trial

Data reflects superior discrimination of the ORBIT score as reported in the Journal of Internal Medicine. nih.gov Specific C-index values for ATRIA and HEMORR₂HAGES for these specific outcomes were not detailed in the provided source.

Molecular Mechanism of Neutralization (Antibody Fragment Binding Affinity)

Idarucizumab neutralizes this compound's anticoagulant effect through a highly specific and potent binding mechanism. tga.gov.au It is a humanized monoclonal antibody fragment that binds directly to this compound and its active acylglucuronide metabolites. drugbank.comfda.gov This binding is characterized by a very high affinity, approximately 350 times greater than this compound's affinity for thrombin. ahajournals.orginternetbookofemergencymedicine.com

The interaction between idarucizumab and this compound is mediated by hydrophobic interactions, hydrogen bonds, and a salt bridge, leading to a rapid on-rate and an extremely slow off-rate. creativebiolabs.netnih.gov This results in the formation of a stable, essentially irreversible complex. tga.gov.auashpublications.org By binding to this compound, idarucizumab prevents the anticoagulant from interacting with thrombin, thereby neutralizing its effect. drugbank.com Importantly, idarucizumab is specific to this compound and does not bind to other thrombin substrates or exhibit any intrinsic procoagulant or anticoagulant activity. creativebiolabs.nettga.gov.auahajournals.org

Table 1: Binding Affinity Comparison

Hemostatic Efficacy Studies (e.g., RE-VERSE AD trial)

The RE-VERSE AD (Reversal Effects of Idarucizumab on Active this compound) trial was a pivotal prospective cohort study that investigated the efficacy of idarucizumab in patients treated with this compound who presented with either life-threatening or uncontrolled bleeding, or who required emergency surgery or urgent procedures. internetbookofemergencymedicine.comwikijournalclub.org

In an interim analysis of the study, the primary endpoint was the maximum percentage reversal of the anticoagulant effect of this compound within four hours. internetbookofemergencymedicine.com The results demonstrated a median maximum reversal of 100%. internetbookofemergencymedicine.comboehringer-ingelheim.com For patients with serious bleeding, the median time to cessation of bleeding was 11.4 hours. internetbookofemergencymedicine.com In the cohort requiring urgent procedures, normal intraoperative hemostasis was achieved in 92% of patients. wikijournalclub.org

The final analysis of the RE-VERSE AD trial, which included 503 patients, confirmed these findings. boehringer-ingelheim.com The median maximum percentage reversal of this compound's anticoagulant effect remained at 100%. boehringer-ingelheim.com In patients with non-intracranial hemorrhage, the median time to bleeding cessation was 2.5 hours. boehringer-ingelheim.com For those undergoing urgent procedures, 93.4% were assessed as having normal hemostasis. boehringer-ingelheim.com

Table 2: Key Efficacy Outcomes from the RE-VERSE AD Trial

Pharmacokinetic-Pharmacodynamic Reversal Dynamics

The administration of idarucizumab leads to an immediate and complete reversal of this compound's anticoagulant effect. ahajournals.orginternetbookofemergencymedicine.com Following intravenous administration, plasma concentrations of unbound this compound are reduced to below the lower limit of quantification almost instantly. fda.gov This rapid neutralization is reflected in the immediate normalization of coagulation parameters that are prolonged by this compound, such as the diluted thrombin time (dTT), ecarin clotting time (ECT), and activated partial thromboplastin time (aPTT). fda.govinternetbookofemergencymedicine.com

The reversal effect is sustained, with coagulation parameters remaining at baseline levels for at least 24 hours in most patients. fda.gov Idarucizumab itself has a biphasic elimination with an initial half-life of about 45 minutes. ahajournals.org Despite this relatively short half-life, its high binding affinity ensures that it effectively sequesters this compound from the plasma. ahajournals.org

Investigation of the this compound Rebound Phenomenon

In some patients, a recurrence of elevated this compound plasma levels and a subsequent increase in clotting times have been observed between 1 and 24 hours after the administration of idarucizumab. This phenomenon, known as the this compound rebound effect, is thought to be caused by the redistribution of this compound from the extravascular compartment back into the plasma after the initial dose of idarucizumab has been cleared.

The risk of this rebound effect appears to be higher in patients with very high initial this compound concentrations and in those with renal insufficiency, which prolongs the half-life of this compound. In cases where the rebound is associated with clinically relevant bleeding, additional doses of idarucizumab may be considered. ahajournals.org

Prothrombin Complex Concentrates (PCCs) Efficacy and Mechanisms

Prothrombin complex concentrates (PCCs) contain varying amounts of vitamin K-dependent coagulation factors, including factors II (prothrombin), VII, IX, and X. The proposed mechanism for reversing this compound's effect is to increase the concentration of thrombin to a level that overcomes the competitive inhibition by this compound. nih.gov

Research on the efficacy of PCCs for this compound reversal has yielded mixed results. Some preclinical studies in animal models have shown that PCCs can reduce bleeding in a dose-dependent manner. nih.govresearchgate.net For instance, a study in a rabbit model demonstrated that PCC administration significantly reduced both bleeding time and total blood loss. researchgate.net

However, a study in healthy human volunteers found that a standard dose of PCC did not reverse the anticoagulant effect of this compound as measured by various coagulation assays. In a porcine trauma model, while a four-factor PCC was effective in reducing blood loss, it was less effective than idarucizumab. ashpublications.orgconfex.com Furthermore, the administration of PCC led to a "supernormal" activation of coagulation, indicating a different and less targeted mechanism of action compared to the specific neutralization by idarucizumab. ashpublications.orgconfex.com

Activated PCC (FEIBA)

Activated prothrombin complex concentrate (aPCC), available as FEIBA (Factor Eight Inhibitor Bypassing Activity), has been investigated as a non-specific reversal agent for this compound. dovepress.com In vitro studies and animal models have shown some promise.

In an in vitro study using blood spiked with this compound, aPCC at a concentration of 1.8 U/mL was found to reduce the prolonged clotting time by approximately one-third. nih.gov Furthermore, aPCC doubled the initial clot growth velocity in these samples. nih.gov Another study demonstrated that aPCC, but not non-activated prothrombin complex concentrate (PCC), shortened the clotting time in blood samples containing this compound. Specifically, aPCC significantly increased the initial rate of clot growth in the presence of this compound.

Preclinical studies in animal models have also provided some supporting evidence. In a rat tail bleeding model, FEIBA was shown to reverse the bleeding time prolongation caused by this compound, even though it did not affect the prolonged activated partial thromboplastin time (aPTT). ahajournals.org Research also suggests that FEIBA may offer the combined effects of PCC and recombinant activated factor VII (rFVIIa). acc.org

However, the evidence is not uniformly positive. One study noted that while FEIBA corrected this compound-mediated prolonged lag-time, it did not correct the endogenous thrombin potential-area under the curve. dovepress.com The efficacy of aPCCs in clinical practice for this compound reversal remains a subject of ongoing investigation, with calls for systematic evaluation through case reports, registries, and eventually, randomized clinical trials to determine the potential benefit for patients. nih.gov

Table 1: Effect of Activated PCC (FEIBA) on this compound-Induced Coagulopathy in a Rat Model

Recombinant Activated Factor VII (rFVIIa)

Recombinant activated factor VII (rFVIIa) has been explored as another potential non-specific strategy for reversing the anticoagulant effects of this compound. Its mechanism involves the activation of Factor X and Factor IX. acc.org

In vitro research has yielded mixed results. One study found that rFVIIa shortened the clotting time in blood samples spiked with this compound. Specifically, a concentration of 2.1 µg/mL resulted in a 12% reduction in clotting time, and tripling this concentration led to a further reduction of 26%. Another study reported that rFVIIa successfully reversed the actions of this compound by reducing the clot initiation time to baseline levels in blood from healthy volunteers. researchgate.net

Conversely, other studies have shown limited efficacy. One in vitro investigation using Sonoclot analysis did not find a certain reversing effect of rFVIIa on this compound-induced anticoagulation. nih.gov In a murine model of intracerebral hemorrhage, rFVIIa did not prevent the expansion of hematoma induced by this compound. acc.org Furthermore, an analysis of off-label use of rFVIIa in 35 clinical trials raised concerns about an increased rate of arterial thromboembolic events compared to placebo, particularly in the elderly. acc.org This highlights the potential risks associated with using non-specific procoagulant agents. acc.org

Table 2: In Vitro Effect of rFVIIa on this compound-Induced Prolonged Clotting Time

Efficacy of Hemodialysis in this compound Clearance

This compound's low plasma protein binding of approximately 35% and its relatively small molecular weight make it amenable to removal by dialysis. dovepress.comahajournals.orgnih.govscispace.com Studies have demonstrated the effectiveness of this approach.

In a study involving patients with end-stage renal disease, a four-hour hemodialysis session was able to remove between 50% and 60% of this compound from the plasma. europa.eu The clearance of this compound via dialysis is proportional to the blood flow rate. europa.eu Another study showed that a four-hour hemodialysis session could remove approximately 49% of total this compound from the central compartment. scispace.com Research comparing intermittent hemodialysis (iHD) with sustained low-efficiency dialysis (SLED) found that SLED removed more this compound per hour than iHD, which is attributed to this compound's large volume of distribution (60-70 L) that requires redistribution for effective removal. karger.com A modeling analysis predicted that a four-hour hemodialysis session would reduce plasma concentrations by 46%. nih.gov

Table 3: this compound Clearance with Hemodialysis

Patient Selection Criteria for Dialysis Reversal

The decision to use hemodialysis for this compound reversal is typically reserved for specific clinical scenarios. It is considered in cases of severe bleeding or overdose, especially when a rapid reversal of anticoagulant effects is necessary. ahajournals.org Patients with renal impairment are particularly good candidates, as their natural clearance of the drug is already compromised. ahajournals.org

A decisional algorithm has been proposed for managing this compound overload in the context of acute kidney injury (AKI). nih.gov This algorithm considers the patient's renal function, bleeding severity, and the urgency of any required surgical procedures. nih.gov In patients with this compound overload and AKI without major bleeding, hemodialysis may be the preferred treatment to remove the drug, potentially avoiding the need for specific antidotes. nih.gov The presence of major bleeding or the need for emergency surgery would, however, prioritize the use of a specific reversal agent like idarucizumab, with hemodialysis considered as a subsequent step if a rebound in this compound levels is a concern. nih.gov

Bleeding Risk in Elderly Patients

Safety Profile in Renal Compromise

The safety of this compound is significantly influenced by renal function, as approximately 80% of the drug is cleared by the kidneys. researchgate.netnih.gov Research has consistently shown that as renal function declines, exposure to this compound increases, which can heighten the risk of bleeding. dovepress.com

A pivotal study on the pharmacokinetics of this compound in relation to renal function demonstrated that patients with moderate renal impairment (creatinine clearance [CrCl] 30-50 mL/min) had about a three-fold higher exposure to the drug compared to individuals with normal renal function. dovepress.com In those with severe renal impairment (CrCl <30 mL/min), this exposure was found to be six times higher, with the drug's half-life more than doubling. dovepress.com This increased exposure is a primary factor for the elevated risk of major bleeding events observed in this patient population. nih.gov

A sub-analysis of the RE-LY (Randomized Evaluation of Long-Term Anticoagulant Therapy) trial, which compared this compound to warfarin for stroke prevention in atrial fibrillation, provided further clinical insights. researchgate.netashpublications.org While the efficacy of this compound was consistent across different levels of renal function, patients with moderate renal impairment taking this compound had higher rates of major bleeding compared to those with normal renal function. researchgate.netashpublications.org Despite this, the incidence of intracranial hemorrhage was lower with this compound than with warfarin across all renal function groups. researchgate.net

Table 1: Impact of Renal Impairment on this compound Exposure

Pharmacokinetic Profiles in Obese and Underweight Patients

The pharmacokinetic properties of this compound can be influenced by extremes in body weight. Studies have indicated that plasma concentrations of this compound tend to be lower in individuals with higher body weight and higher in those with lower body weight.

Efficacy and Safety in Extreme Body Mass Indices

The clinical relevance of altered this compound pharmacokinetics at the extremes of body weight has been a key area of research. Subgroup analyses of major clinical trials have provided insights into the efficacy and safety of this compound in these populations.

In the RE-LY trial, the efficacy of this compound in preventing stroke and systemic embolism was found to be consistent across various body weight categories. nih.gov Similarly, a subanalysis of the RE-DUAL PCI trial, which evaluated this compound-based dual therapy in patients with atrial fibrillation who had undergone percutaneous coronary intervention, found that the reduction in bleeding rates with this compound compared to warfarin-based triple therapy was consistent across different BMI categories. globalrph.com

However, safety outcomes have shown some variability. A real-world retrospective cohort study of atrial fibrillation patients with severe obesity (BMI >40 kg/m ² or weight >120 kg) found that this compound was effective in reducing thromboembolism and mortality compared to warfarin, but was associated with an increased risk of bleeding. ahajournals.orgnih.gov In contrast, a pooled analysis of studies in patients undergoing major orthopedic surgery showed no significant differences in the efficacy and safety of this compound compared to enoxaparin in patients with a BMI >30 kg/m ². europa.eu For underweight patients, there is a concern for increased bleeding risk, which may be linked to the higher drug exposure observed in this group. wikijournalclub.org

Table 2: Efficacy and Safety of this compound in Patients with Severe Obesity (BMI >40 kg/m ² or Weight >120 kg) vs. Warfarin (Real-World Data)

Data from a retrospective cohort study. nih.gov

Patients with Malignancy

The treatment of cancer-associated thrombosis (CAT) has traditionally relied on low-molecular-weight heparin (LMWH). globalrph.comdovepress.com However, research has increasingly explored the role of direct oral anticoagulants (DOACs), including this compound, in this patient population.

Subgroup analyses of the RE-COVER and RE-COVER II trials, which compared this compound to warfarin for the treatment of acute venous thromboembolism (VTE), included patients with active cancer. nice.org.ukacc.orggarfieldregistry.org In a pooled analysis of these trials, the efficacy of this compound in preventing recurrent VTE in patients with cancer was found to be similar to that of warfarin. nice.org.uk

Several meta-analyses have compared DOACs as a class with LMWH for the treatment of CAT. One meta-analysis of randomized controlled trials found that DOACs were associated with a nonsignificantly lower risk of recurrent VTE compared to LMWH, but with a nonsignificantly higher risk of major bleeding and clinically relevant non-major bleeding. ashpublications.org Another meta-analysis that included eight trials concluded that DOACs significantly reduced the risk of VTE recurrence compared to LMWH without a significant increase in major bleeding. japscjournal.com It is important to note that some meta-analyses have limited data specifically on this compound compared to other DOACs like apixaban and rivaroxaban. japscjournal.comjnccn.org The risk of bleeding, particularly in patients with gastrointestinal malignancies, remains a key consideration when using DOACs in the context of cancer. japscjournal.com

Patients with Mechanical Heart Valves

Research into the use of this compound as an alternative to warfarin in patients with mechanical heart valves has been highlighted by the RE-ALIGN trial. acc.org2minutemedicine.comnih.gov This prospective, randomized, phase 2 dose-validation study was designed to evaluate the safety and pharmacokinetics of oral this compound etexilate in this patient population. acc.orgnih.gov The trial included patients who had recently undergone aortic or mitral valve replacement (within seven days) and those who had their valve replacement at least three months prior. acc.org Participants were randomized to receive either this compound or warfarin. acc.org

The RE-ALIGN trial was terminated prematurely due to a notable excess of thromboembolic and bleeding events in the this compound group compared to the warfarin group. acc.org2minutemedicine.com The findings from the trial indicated that this compound was not effective in preventing thromboembolic complications in this patient population and was associated with a heightened risk of bleeding compared to warfarin. acc.org Specifically, ischemic or unspecified stroke occurred in 5% of patients in the this compound group, while no such events were observed in the warfarin group. acc.orgcardioaragon.com Major bleeding was also more frequent in the this compound group (4%) compared to the warfarin group (2%). acc.orgcardioaragon.com

Table 1: Key Findings from the RE-ALIGN Trial

Data sourced from the RE-ALIGN trial as reported in multiple sources. acc.org2minutemedicine.comcardioaragon.commedscape.com

Patients with Thrombophilia

The investigation of this compound in patients with thrombophilia, an inherited or acquired predisposition to blood clots, has yielded more promising results compared to its use in patients with mechanical heart valves. A post-hoc analysis of several large clinical trials has suggested that the efficacy and safety of this compound are not significantly influenced by the presence of thrombophilia. ahajournals.org

In pediatric populations, the DIVERSITY trial, a phase IIb/III study, demonstrated that a three-month course of this compound was non-inferior to standard of care for acute venous thromboembolism (VTE) in children, including those with thrombophilia. ashpublications.orgnih.govnih.gov A subsequent single-arm, phase III study on secondary VTE prevention showed that up to 12 months of this compound therapy had a favorable safety profile in this population. ashpublications.orgnih.gov In the DIVERSITY trial's thrombophilia subgroup, 36% of patients treated with this compound met the primary endpoint, compared to 22% of those on standard of care. ashpublications.orgnih.govnih.gov These findings suggest that this compound could be a suitable long-term anticoagulant for children with thrombophilia. ashpublications.orgnih.gov

A subgroup analysis of the RE-MEDY trial, which focused on the extended treatment of VTE, also supported the use of this compound in patients with thrombophilia. researchgate.net The analysis showed that this compound was non-inferior to warfarin in preventing recurrent VTE and VTE-related deaths in this patient group. researchgate.net However, for patients with antiphospholipid syndrome (APS), a specific type of acquired thrombophilia, caution is still advised. While some studies have included patients with APS, international guidelines generally recommend against the routine use of direct oral anticoagulants (DOACs), including this compound, in all APS patients, particularly those with high-risk features like triple positivity for antiphospholipid antibodies. nih.govfrontiersin.orgmdpi.com

Table 2: Thrombophilia Types in Pediatric this compound Studies (DIVERSITY and Secondary Prevention Study)

Data represents the percentage of patients with each type of thrombophilia within the respective studies. nih.gov

Patients Undergoing Percutaneous Coronary Intervention (PCI)

For patients with non-valvular atrial fibrillation who undergo percutaneous coronary intervention (PCI), the RE-DUAL PCI trial has provided significant insights into the use of this compound. acc.orgbjcardio.co.ukahajournals.org This randomized trial compared dual antithrombotic therapy with this compound and a P2Y12 inhibitor (clopidogrel or ticagrelor) to traditional triple therapy with warfarin, a P2Y12 inhibitor, and aspirin. acc.orgbjcardio.co.uk

The primary finding of the RE-DUAL PCI trial was a significant reduction in the incidence of major or clinically relevant non-major bleeding events with this compound dual therapy compared to warfarin triple therapy. acc.orgbjcardio.co.uk This was observed for both doses of this compound studied. bjcardio.co.uk The trial also demonstrated that dual therapy with this compound was non-inferior to triple therapy with warfarin for the composite endpoint of death, myocardial infarction, stroke, systemic embolism, or unplanned revascularization. acc.orgjacc.org

The benefits of this compound dual therapy in reducing bleeding were consistent across various patient subgroups, including those with acute coronary syndrome (ACS) versus elective PCI, and those receiving either clopidogrel or ticagrelor. acc.org Sub-analyses of the RE-DUAL PCI trial have also explored outcomes in patients with diabetes and varying levels of renal function, confirming the favorable safety profile of this compound dual therapy in these specific populations. jacc.orgjacc.orgicrjournal.com These findings support the use of a dual therapy regimen with this compound as an alternative to traditional triple therapy to enhance safety without compromising efficacy in patients with atrial fibrillation following PCI. bjcardio.co.uk

Table 3: Key Outcomes of the RE-DUAL PCI Trial

Data sourced from the RE-DUAL PCI trial. acc.orgbjcardio.co.uk

Addressing Inter-individual Variability in Clinical Practice

While this compound offers more predictable pharmacokinetics compared to warfarin, inter-individual variability in plasma concentrations can still occur. synergypublishers.comcsnn.eumdpi.comresearchgate.net This variability can be influenced by factors such as renal function, age, body weight, and genetic polymorphisms in genes involved in drug transport and metabolism, such as CES1 and ABCB1. dovepress.comsynergypublishers.comcsnn.eumdpi.commdpi.com

Studies have investigated the contribution of these genetic polymorphisms to variations in this compound exposure. For example, polymorphisms in CES1, which is involved in the activation of the this compound etexilate prodrug, have been associated with differences in this compound concentrations. csnn.eumdpi.com Similarly, ABCB1 (encoding for P-glycoprotein), a transporter involved in this compound's absorption and excretion, can also contribute to variability. csnn.eumdpi.com Addressing this variability in clinical practice is challenging because routine monitoring of this compound levels is generally not required. thrombosiscanada.camdpi.com However, understanding the factors contributing to variability is crucial for identifying patients who may be at higher risk of suboptimal anticoagulation or increased bleeding risk. mdpi.com

Development of Point-of-Care Assays for Anticoagulant Effect

The absence of a widely available, standardized point-of-care (POC) test to reliably assess this compound's anticoagulant effect poses a challenge in situations where such information is critical, such as in emergency settings, before urgent procedures, or in cases of suspected overdose. thrombosiscanada.canih.govpoctinnovators.comfu-berlin.de While routine monitoring is not needed for most patients, a rapid assessment of anticoagulant status can guide clinical decision-making, particularly regarding the administration of reversal agents or the timing of interventions. poctinnovators.com

Current laboratory tests can be affected by this compound, but their sensitivity and correlation with this compound levels vary. thrombosiscanada.ca Dilute thrombin time (dTT) and Ecarin-based assays are more specific for quantifying this compound's effect, but they are not universally available as POC tests, and established therapeutic ranges for interpretation are still evolving. thrombosiscanada.canih.govpoctinnovators.comfu-berlin.de Research is ongoing to develop and validate POC assays that can provide rapid and reliable estimates of this compound's anticoagulant effect. Some studies have explored the utility of existing POC coagulation tests, such as certain automated thromboelastography systems, but their accuracy and correlation with this compound concentrations require further validation. fu-berlin.deahajournals.orgahajournals.org

Cost-Effectiveness Analyses

Cost-effectiveness analyses (CEAs) evaluate the value of a medical intervention by comparing its costs and outcomes (often measured in quality-adjusted life years - QALYs) against alternative interventions. nih.govsmw.chaafp.org For this compound, CEAs frequently compare it to traditional anticoagulants like warfarin, particularly in the context of stroke prevention in patients with atrial fibrillation (AF). nih.govsmw.chaafp.orgbmj.comahajournals.org

Studies have utilized decision-analysis models, such as Markov models, to simulate the long-term costs and outcomes of different antithrombotic therapies in hypothetical patient cohorts. nih.govsmw.ch These models incorporate data from clinical trials, including event rates (e.g., stroke, bleeding) and associated costs. nih.govsmw.chbmj.com

Several CEAs have concluded that this compound can be cost-effective in specific patient populations. For instance, in patients with AF at high risk of stroke or high risk of hemorrhage, this compound 150 mg twice daily was found to be cost-effective compared to warfarin, especially when the quality of International Normalized Ratio (INR) control with warfarin was suboptimal. nih.govaafp.org One study in a hypothetical cohort of 70-year-old patients with AF estimated the cost of this compound at US $9 per day and found it cost-effective for high-risk patients unless INR control with warfarin was excellent (time in therapeutic range >72.6%). nih.gov For patients with moderate stroke risk, warfarin was often found to be cost-effective unless INR control was poor (time in therapeutic range <57.1%). nih.gov

Analyses conducted in different healthcare systems have yielded varying incremental cost-effectiveness ratios (ICERs). In a Swiss context, this compound was considered cost-effective compared to vitamin K antagonists, with estimated ICERs per QALY gained ranging from CHF 9,702 for the 150 mg dose to CHF 25,108 for the 110 mg dose. smw.ch A sequential dosage scheme (150 mg up to age 80, then 110 mg) resulted in an ICER of CHF 10,215 per QALY. smw.ch The higher drug cost of this compound was reported to be offset by savings from reduced INR monitoring and lower costs associated with clinical events. smw.ch In the UK, ICERs for this compound etexilate versus warfarin were estimated at £4831/QALY for patients under 80 and £7090/QALY for those aged 80 or older. bmj.com Probabilistic sensitivity analyses in the UK context indicated a high probability of this compound being cost-effective at a willingness-to-pay threshold of £20,000/QALY gained, particularly for patients under 80. bmj.com

These analyses highlight that the cost-effectiveness of this compound is influenced by factors such as stroke risk, bleeding risk, age, and the quality of INR control achieved with warfarin. nih.govaafp.orgbmj.com

Budget Impact Analyses

BIAs consider factors such as drug costs, costs associated with monitoring (e.g., INR testing for warfarin), and costs related to managing clinical events (e.g., strokes, bleeding events). ncpe.ienih.gov Models are developed to project costs based on estimated patient populations and treatment uptake rates. researchgate.netnih.gov

Studies have shown that while the direct drug cost of this compound is often higher than that of warfarin, potential cost savings can arise from a reduction in monitoring requirements and a decrease in the incidence of costly events, particularly intracranial hemorrhage. bmj.comncpe.ie

A budget impact analysis in Italy comparing this compound 150 mg BID with rivaroxaban 20 mg in patients with non-valvular atrial fibrillation (NVAF) suggested that higher prescription volumes of this compound could lead to cost savings for the Italian National Health Service. This was attributed to fewer intracranial hemorrhage and major extracranial bleeding events offsetting the incremental drug cost. The analysis estimated an annual saving per patient treated with this compound (€1,052.78) compared to rivaroxaban (€1,161.23). The total annual cost for the Italian NHS was predicted to decrease by 3.8% if this compound prescription increased to 70% and by 6.7% if it increased to 100%.

Another study focusing on the budget impact of switching eligible patients with AF to lower-dose this compound (110 mg) versus reduced doses of apixaban or rivaroxaban in the Netherlands estimated significant cost savings over a 3-year horizon. nih.gov Switching from reduced-dose apixaban or rivaroxaban to lower-dose this compound resulted in estimated cost savings of €157 thousand or €72 thousand per 100 patient-years, respectively, or a total of €146 million for the total Dutch population over 3 years. nih.gov The budget impact in this study was primarily driven by event costs. nih.gov

An earlier budget impact estimate in the UK projected that the net budget impact to the Health Service Executive (HSE) of this compound could increase over time, driven by the uptake of the drug. ncpe.ie However, this estimate was considered potentially underestimated, with the possibility of exceeding higher figures by 2015. ncpe.ie

These BIAs demonstrate the complex financial considerations associated with the adoption and utilization of this compound within healthcare systems, highlighting the interplay between drug costs and the costs of clinical event management. ncpe.ienih.gov

Cost-Effectiveness Analyses

Cost-effectiveness analyses (CEAs) evaluate the value of a medical intervention by comparing its costs and outcomes (often measured in quality-adjusted life years - QALYs) against alternative interventions. nih.govsmw.chaafp.org For this compound, CEAs frequently compare it to traditional anticoagulants like warfarin, particularly in the context of stroke prevention in patients with atrial fibrillation (AF). nih.govsmw.chaafp.orgbmj.comahajournals.org

Studies have utilized decision-analysis models, such as Markov models, to simulate the long-term costs and outcomes of different antithrombotic therapies in hypothetical patient cohorts. nih.govsmw.ch These models incorporate data from clinical trials, including event rates (e.g., stroke, bleeding) and associated costs. nih.govsmw.chbmj.com

Several CEAs have concluded that this compound can be cost-effective in specific patient populations. For instance, in patients with AF at high risk of stroke or high risk of hemorrhage, this compound 150 mg twice daily was found to be cost-effective compared to warfarin, especially when the quality of International Normalized Ratio (INR) control with warfarin was suboptimal. nih.govaafp.org One study in a hypothetical cohort of 70-year-old patients with AF estimated the cost of this compound at US $9 per day and found it cost-effective for high-risk patients unless INR control with warfarin was excellent (time in therapeutic range >72.6%). nih.gov For patients with moderate stroke risk, warfarin was often found to be cost-effective unless INR control was poor (time in therapeutic range <57.1%). nih.gov

Analyses conducted in different healthcare systems have yielded varying incremental cost-effectiveness ratios (ICERs). In a Swiss context, this compound was considered cost-effective compared to vitamin K antagonists, with estimated ICERs per QALY gained ranging from CHF 9,702 for the 150 mg dose to CHF 25,108 for the 110 mg dose. smw.ch A sequential dosage scheme (150 mg up to age 80, then 110 mg) resulted in an ICER of CHF 10,215 per QALY. smw.ch The higher drug cost of this compound was reported to be offset by savings from reduced INR monitoring and lower costs associated with clinical events. smw.ch In the UK, ICERs for this compound etexilate versus warfarin were estimated at £4831/QALY for patients under 80 and £7090/QALY for those aged 80 or older. bmj.com Probabilistic sensitivity analyses in the UK context indicated a high probability of this compound being cost-effective at a willingness-to-pay threshold of £20,000/QALY gained, particularly for patients under 80. bmj.com

These analyses highlight that the cost-effectiveness of this compound is influenced by factors such as stroke risk, bleeding risk, age, and the quality of INR control achieved with warfarin. nih.govaafp.orgbmj.com

Budget Impact Analyses

BIAs consider factors such as drug costs, costs associated with monitoring (e.g., INR testing for warfarin), and costs related to managing clinical events (e.g., strokes, bleeding events). ncpe.ienih.gov Models are developed to project costs based on estimated patient populations and treatment uptake rates. researchgate.netnih.gov

Studies have shown that while the direct drug cost of this compound is often higher than that of warfarin, potential cost savings can arise from a reduction in monitoring requirements and a decrease in the incidence of costly events, particularly intracranial hemorrhage. bmj.comncpe.ie

A budget impact analysis in Italy comparing this compound 150 mg BID with rivaroxaban 20 mg in patients with non-valvular atrial fibrillation (NVAF) suggested that higher prescription volumes of this compound could lead to cost savings for the Italian National Health Service. This was attributed to fewer intracranial hemorrhage and major extracranial bleeding events offsetting the incremental drug cost. The analysis estimated an annual saving per patient treated with this compound (€1,052.78) compared to rivaroxaban (€1,161.23). The total annual cost for the Italian NHS was predicted to decrease by 3.8% if this compound prescription increased to 70% and by 6.7% if it increased to 100%.

Another study focusing on the budget impact of switching eligible patients with AF to lower-dose this compound (110 mg) versus reduced doses of apixaban or rivaroxaban in the Netherlands estimated significant cost savings over a 3-year horizon. nih.gov Switching from reduced-dose apixaban or rivaroxaban to lower-dose this compound resulted in estimated cost savings of €157 thousand or €72 thousand per 100 patient-years, respectively, or a total of €146 million for the total Dutch population over 3 years. nih.gov The budget impact in this study was primarily driven by event costs. nih.gov

An earlier budget impact estimate in the UK projected that the net budget impact to the Health Service Executive (HSE) of this compound could increase over time, driven by the uptake of the drug. ncpe.ie However, this estimate was considered potentially underestimated, with the possibility of exceeding higher figures by 2015. ncpe.ie

These BIAs demonstrate the complex financial considerations associated with the adoption and utilization of this compound within healthcare systems, highlighting the interplay between drug costs and the costs of clinical event management. ncpe.ienih.gov