Warfarin analogs target disulfide bond-forming enzymes and suggest a residue important for quinone and coumarin binding.

Disulfide bond formation has a central role in protein folding of both eukaryotes and prokaryotes. In bacteria, disulfide bonds are catalyzed by DsbA and DsbB/VKOR enzymes. First, DsbA, a periplasmic disulfide oxidoreductase, introduces disulfide bonds into substrate proteins. Then, the membrane enzyme, either DsbB or VKOR, regenerate DsbA's activity by the formation of de novo disulfide bonds which reduce quinone. We have previously performed a high-throughput chemical screen and identified a family of warfarin analogs that target either bacterial DsbB or VKOR. In this work, we expressed functional human VKORc1 in Escherichia coli and performed a structure-activity-relationship analysis to study drug selectivity between bacterial and mammalian enzymes. We found that human VKORc1 can function in E. coli by removing two positive residues, allowing the search for novel anticoagulants using bacteria. We also found one warfarin analog capable of inhibiting both bacterial DsbB and VKOR and a second one antagonized only the mammalian enzymes when expressed in E. coli. The difference in the warfarin structure suggests that substituents at positions three and six in the coumarin ring can provide selectivity between the bacterial and mammalian enzymes. Finally, we identified the two amino acid residues responsible for drug binding. One of these is also essential for de novo disulfide bond formation in both DsbB and VKOR enzymes. Our studies highlight a conserved role of this residue in de novo disulfide-generating enzymes and enable the design of novel anticoagulants or antibacterials using coumarin as a scaffold.

Efficacy and Safety of Non-Vitamin-K Antagonist Oral Anticoagulants Versus Warfarin Across the Spectrum of Body Mass Index and Body Weight: An Individual Patient Data Meta-Analysis of 4 Randomized Clinical Trials of Patients With Atrial Fibrillation.

BACKGROUND: The efficacy and safety of non-vitamin-K antagonist oral anticoagulants (NOACs) across the spectrum of body mass index (BMI) and body weight (BW) remain uncertain. METHODS: We analyzed data from COMBINE AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation), which pooled patient-level data from the 4 pivotal randomized trials of NOAC versus warfarin in patients with atrial fibrillation. The primary efficacy and safety outcomes were stroke or systemic embolic events (stroke/SEE) and major bleeding, respectively; secondary outcomes were ischemic stroke/SEE, intracranial hemorrhage, death, and the net clinical outcome (stroke/SEE, major bleeding, or death). Each outcome was examined across BMI and BW. Because few patients had a BMI <18.5 kg/m2 (n=598), the primary analyses were restricted to those with a BMI ≥18.5 kg/m2. RESULTS: Among 58 464 patients, the median BMI was 28.3 (interquartile range, 25.2-32.2) kg/m2, and the median BW was 81.0 (interquartile range, 70.0-94.3) kg. The event probability of stroke/SEE was lower at a higher BMI irrespective of treatment, whereas the probability of major bleeding was lower at a higher BMI with warfarin but relatively unchanged across BMI with NOACs. NOACs reduced stroke/SEE overall (adjusted hazard ratio [HRadj], 0.80 [95% CI, 0.73-0.88]; P<0.001), with a generally consistent effect across BMI (Ptrend across HRs, 0.48). NOACs also reduced major bleeding overall (HRadj, 0.88 [95% CI, 0.82-0.94]; P<0.001), but with attenuation of the benefit at a higher BMI (trend test across BMI [Ptrend], 0.003). The overall treatment effects of NOACs versus warfarin for secondary outcomes were consistent across BMI, with the exception of the net clinical outcome and death. While these outcomes were overall reduced with NOACs (net clinical outcome, HRadj, 0.91 [95% CI, 0.87-0.95]; P<0.001; death, HRadj, 0.91 [95% CI, 0.86-0.97]; P=0.003), these benefits were attenuated at higher BMI (Ptrend, 0.001 and 0.08, respectively). All findings were qualitatively similar when analyzed across BW. CONCLUSIONS: The treatment effect of NOACs versus warfarin in atrial fibrillation is generally consistent for stroke/SEE across the spectrum of BMI and BW, whereas the reduction in major bleeding is attenuated in those with higher BMI or BW. Death and the net clinical outcome are overall reduced with NOACs over warfarin, although there remain uncertainties for these outcomes at a very high BMI and BW.

2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines.

AIM: The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation. METHODS: A comprehensive literature search was conducted from May 12, 2022, to November 3, 2022, encompassing studies, reviews, and other evidence conducted on human subjects that were published in English from PubMed, EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. Additional relevant studies, published through November 2022, during the guideline writing process, were also considered by the writing committee and added to the evidence tables, where appropriate. STRUCTURE: Atrial fibrillation is the most sustained common arrhythmia, and its incidence and prevalence are increasing in the United States and globally. Recommendations from the "2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" and the "2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation" have been updated with new evidence to guide clinicians. In addition, new recommendations addressing atrial fibrillation and thromboembolic risk assessment, anticoagulation, left atrial appendage occlusion, atrial fibrillation catheter or surgical ablation, and risk factor modification and atrial fibrillation prevention have been developed.

Comparative Effectiveness and Safety of Direct Oral Anticoagulants and Warfarin in Patients With Atrial Fibrillation and Chronic Liver Disease: A Nationwide Cohort Study.

BACKGROUND: The benefit-risk profile of direct oral anticoagulants (DOACs) compared with warfarin, and between DOACs in patients with atrial fibrillation (AF) and chronic liver disease is unclear. METHODS: We conducted a new-user, retrospective cohort study of patients with AF and chronic liver disease who were enrolled in a large, US-based administrative database between January 1, 2011, and December 31, 2017. We assessed the effectiveness and safety of DOACs (as a class and individually) compared with warfarin, and between DOACs in patients with AF and chronic liver disease. The primary outcomes were hospitalization for ischemic stroke/systemic embolism and hospitalization for major bleeding. Inverse probability treatment weights were used to balance the treatment groups on measured confounders. RESULTS: Overall, 10 209 participants were included, with 4421 (43.2%) on warfarin, 2721 (26.7%) apixaban, 2211 (21.7%) rivaroxaban, and 851 (8.3%) dabigatran. The incidence rates per 100 person-years for ischemic stroke/systemic embolism were 2.2, 1.4, 2.6, and 4.4 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. The incidence rates per 100 person-years for major bleeding were 7.9, 6.5, 9.1, and 15.0 for DOACs as a class, apixaban, rivaroxaban, and warfarin, respectively. After inverse probability treatment weights, the risk of hospitalization for ischemic stroke/systemic embolism was significantly lower between DOACs as a class (hazard ratio [HR], 0.64 [95% CI, 0.46-0.90]) or apixaban (HR, 0.40 [95% CI, 0.19-0.82]) compared with warfarin, but not significantly different between rivaroxaban versus warfarin (HR, 0.76 [95% CI, 0.47-1.21]) or rivaroxaban versus apixaban (HR, 1.73 [95% CI, 0.91-3.29]). Compared with warfarin, the risk of hospitalization for major bleeding was lower with DOACs as a class (HR, 0.69 [95% CI, 0.58-0.82]), apixaban (HR, 0.60 [95% CI, 0.46-0.78]), and rivaroxaban (HR, 0.79 [95% CI, 0.62-1.0]). However, the risk of hospitalization for major bleeding was higher for rivaroxaban versus apixaban (HR, 1.59 [95% CI, 1.18-2.14]). CONCLUSIONS: Among patients with AF and chronic liver disease, DOACs as a class were associated with lower risks of hospitalization for ischemic stroke/systemic embolism and major bleeding versus warfarin. However, the incidence of clinical outcomes among patients with AF and chronic liver disease varied between individual DOACs and warfarin, and in head-to-head DOAC comparisons.

Massively parallel characterization of CYP2C9 variant enzyme activity and abundance.

CYP2C9 encodes a cytochrome P450 enzyme responsible for metabolizing up to 15% of small molecule drugs, and CYP2C9 variants can alter the safety and efficacy of these therapeutics. In particular, the anti-coagulant warfarin is prescribed to over 15 million people annually and polymorphisms in CYP2C9 can affect individual drug response and lead to an increased risk of hemorrhage. We developed click-seq, a pooled yeast-based activity assay, to test thousands of variants. Using click-seq, we measured the activity of 6,142 missense variants in yeast. We also measured the steady-state cellular abundance of 6,370 missense variants in a human cell line by using variant abundance by massively parallel sequencing (VAMP-seq). These data revealed that almost two-thirds of CYP2C9 variants showed decreased activity and that protein abundance accounted for half of the variation in CYP2C9 function. We also measured activity scores for 319 previously unannotated human variants, many of which may have clinical relevance.

The comparative efficacy and safety of factor Xa inhibitors and warfarin for primary thromboprophylaxis in multiple myeloma patients undergoing immunomodulatory therapy.

There are limited data on the optimal choice of anticoagulation in multiple myeloma (MM) patients receiving immunomodulatory drugs (IMiDs). We conducted a propensity score-matched cohort study using the TriNetX database to compare the efficacy and safety of factor Xa inhibitors and warfarin in this patient population. Compared to warfarin, factor Xa inhibitors had a similar risk of deep vein thrombosis (hazard ratio [HR]: 1.11 [95% CI: 0.50-2.46]) or pulmonary embolism (HR: 1.08 [95% CI: 0.59-2.00]). There were no differences in the risk of gastrointestinal or intracranial bleeding. Factor Xa inhibitor-treated patients had lower all-cause mortality (HR: 0.56 [95% CI: 0.36-0.86]) compared with warfarin. These data suggest that factor Xa inhibitors had similar safety and efficacy compared with warfarin for MM patients on IMiDs.

Thermal effects and drugs competition on the palmitate binding capacity of human serum albumin.

Human serum albumin (HSA) is the most abundant plasma protein of the circulatory system. It is a multidomain, multifunctional protein that, combining diverse affinities and wide specificity, binds, stores, and transports a variety of biological compounds, pharmacores, and fatty acids. HSA is finding increasing uses in drug-delivery due to its ability to carry functionalized ligands and prodrugs. All this raises the question of competition for binding sites occupancy in case of multiple ligands, which in turn influences the protein structure/dynamic/function relationship and also has an impact on the biomedical applications. In this work, the effects of interactive binding of palmitic acid (PA), warfarin (War) and ibuprofen (Ibu) on the thermal stability of HSA were studied using DSC, ATR-FTIR, and EPR. PA is a high-affinity physiological ligand, while the two drugs are widely used for their anticoagulant (War) and anti-inflammatory (Ibu) efficacy, and are exogenous compounds that accommodate in the deputed drug site DS1 and DS2, respectively overlapping with some of the fatty acid binding sites. The results indicate that HSA acquires the highest thermal stability when it is fully saturated with PA. The binding of this physiological ligand does not hamper the binding of War or Ibu to the native state of the protein. In addition, the three ligands bind simultaneously, suggesting a synergic cooperative influence due to allosteric effects. The increased thermal stability subsequent to binary and multiple ligands binding moderates protein aggregation propensity and restricts protein dynamics. The biophysics findings provide interesting features about protein stability, aggregation, and dynamics in interaction with multiple ligands and are relevant in drug-delivery.

The optimal antithrombotic strategy for post-stroke patients with atrial fibrillation and extracranial artery stenosis-a nationwide cohort study.

BACKGROUND: In post-stroke atrial fibrillation (AF) patients who have indications for both oral anticoagulant (OAC) and antiplatelet agent (AP), e.g., those with carotid artery stenosis, there is debate over the best antithrombotic strategy. We aimed to compare the risks of ischemic stroke, composite of ischemic stroke/major bleeding and composite of ischemic stroke/intracranial hemorrhage (ICH) between different antithrombotic strategies. METHODS: This study included post-stroke AF patients with and without extracranial artery stenosis (ECAS) (n = 6390 and 28,093, respectively) identified from the Taiwan National Health Insurance Research Database. Risks of clinical outcomes and net clinical benefit (NCB) with different antithrombotic strategies were compared to AP alone. RESULTS: The risk of recurrent ischemic stroke was higher for patients with ECAS than those without (12.72%/yr versus 10.60/yr; adjusted hazard ratio [aHR] 1.104, 95% confidence interval [CI] 1.052-1.158, p < 0.001). For patients with ECAS, when compared to AP only, non-vitamin K antagonist oral anticoagulant (NOAC) monotherapy was associated with lower risks for ischaemic stroke (aHR 0.551, 95% CI 0.454-0.669), the composite of ischaemic stroke/major bleeding (aHR 0.626, 95% CI 0.529-0.741) and the composite of ischaemic stroke/ICH (aHR 0.577, 95% CI 0.478-0.697), with non-significant difference for major bleeding and ICH. When compared to AP only, warfarin monotherapy was associated with higher risks of major bleeding (aHR 1.521, 95% CI 1.231-1.880), ICH (aHR 2.045, 95% CI 1.329-3.148), and the composite of ischaemic stroke and major bleeding. With combination of AP plus warfarin, there was an increase in ischaemic stroke, major bleeding, and the composite outcomes, when compared to AP only. NOAC monotherapy was the only approach associated with a positive NCB, while all other options (warfarin, combination of AP-OAC) were associated with negative NCB. CONCLUSIONS: For post-stroke AF patients with ECAS, NOAC monotherapy was associated with lower risks of adverse outcomes and a positive NCB. Combination of AP with NOAC or warfarin did not offer any benefit, but more bleeding especially with AP-warfarin combination therapy.

Comparative Safety and Effectiveness of Warfarin or Rivaroxaban Versus Apixaban in Patients With Advanced CKD and Atrial Fibrillation: Nationwide US Cohort Study.

RATIONALE & OBJECTIVE: Head-to-head data comparing the effectiveness and safety of oral anticoagulants in patients with atrial fibrillation (AF) and advanced chronic kidney disease (CKD) are lacking. We compared the safety and effectiveness of warfarin or rivaroxaban versus apixaban in patients with AF and non-dialysis-dependent CKD stage 4/5. STUDY DESIGN: Propensity score-matched cohort study. SETTING & PARTICIPANTS: 2 nationwide US claims databases, Medicare and Optum's deidentified Clinformatics Data Mart Database, were searched for the interval from January 1, 2013, through March 31, 2022, for patients with nonvalvular AF and CKD stage 4/5 who initiated warfarin versus apixaban (matched cohort, n=12,488) and rivaroxaban versus apixaban (matched cohort, n = 5,720). EXPOSURES: Warfarin, rivaroxaban, or apixaban. OUTCOMES: Primary outcomes included major bleeding and ischemic stroke. Secondary outcomes included all-cause mortality, major gastrointestinal bleeding, and intracranial bleeding. ANALYTICAL APPROACH: Cox regression was used to estimate HRs, and 1:1 propensity-score matching was used to adjust for 80 potential confounders. RESULTS: Compared with apixaban, warfarin initiation was associated with a higher rate of major bleeding (HR, 1.85; 95% CI, 1.59-2.15), including major gastrointestinal bleeding (1.86; 1.53-2.25) and intracranial bleeding (2.15; 1.42-3.25). Compared with apixaban, rivaroxaban was also associated with a higher rate of major bleeding (1.69; 1.33-2.15). All-cause mortality was similar for warfarin (1.08; 0.98-1.18) and rivaroxaban (0.94; 0.81-1.10) versus apixaban. Furthermore, no statistically significant differences for ischemic stroke were observed for warfarin (1.14; 0.83-1.57) or rivaroxaban (0.71; 0.40-1.24) versus apixaban, but the CIs were wide. Similar results were observed for warfarin versus apixaban in the positive control cohort of patients with CKD stage 3, consistent with randomized trial findings. LIMITATIONS: Few ischemic stroke events, potential residual confounding. CONCLUSIONS: In patients with AF and advanced CKD, rivaroxaban and warfarin were associated with higher rates of major bleeding compared with apixaban, suggesting a superior safety profile for apixaban in this high-risk population. PLAIN-LANGUAGE SUMMARY: Different anticoagulants have been shown to reduce the risk of stroke in patients with atrial fibrillation, such as warfarin and direct oral anticoagulants like apixaban and rivaroxaban. Unfortunately, the large-scale randomized trials that compared direct anticoagulants versus warfarin excluded patients with advanced chronic kidney disease. Therefore, the comparative safety and effectiveness of warfarin, apixaban, and rivaroxaban are uncertain in this population. In this study, we used administrative claims data from the United States to answer this question. We found that warfarin and rivaroxaban were associated with increased risks of major bleeding compared with apixaban. There were few stroke events, with no major differences among the 3 drugs in the risk of stroke. In conclusion, this study suggests that apixaban has a better safety profile than warfarin and rivaroxaban.

Risk of ocular neovascular conversion and systemic bleeding complications in patients with AMD on DOACs or Warfarin.

PURPOSE: Conversion to neovascular disease in patients with non-neovascular age-related macular degeneration (AMD) initiated on direct oral anticoagulants (DOAC) compared to matched patients treated with warfarin. DESIGN: Retrospective cohort study. SUBJECTS, PARTICIPANTS, AND/OR CONTROLS: The study included 20,300 patients and 13,387 patients with non-neovascular AMD initiated on DOACs or warfarin, respectively, before propensity score matching (PSM). METHODS, INTERVENTION, OR TESTING: TriNetX (Cambridge, MA, USA), was used to identify patients diagnosed with non-neovascular AMD stratified by treatment with DOACs or warfarin with at least six months of follow-up. Propensity score matching was performed to control for baseline demographics and medical comorbidities. MAIN OUTCOME MEASURES: Relative risk (RR) of developing neovascular AMD, macular hemorrhage (MH), vitreous hemorrhage (VH), and requiring an ocular intervention (intravitreal anti-vascular endothelial growth factor (VEGF) therapy or pars plana vitrectomy (PPV)) within six months and one year. Patients with chronic atrial fibrillation (AF) on anticoagulation were separately evaluated for the same measures within 5 years after initiating therapy. RESULTS: Treatment with warfarin was associated with higher risk of developing neovascular AMD at six months (RR,1.24, 95% CI, 1.12 - 1.39; P<.001) and one year (RR, 1.26, 95% CI, 1.14 - 1.40; P<.001) when compared to matched patients treated with DOACs. There was an increased risk of requiring intravitreal anti-VEGF therapy (6 months: RR, 1.30; 95% CI, 1.13-1.49; P<.001; 1 year: RR, 1.31, 95% CI, 0.72 - 2.05; P<.001) and PPV (6 months: RR, 1.16; 95% CI, 1.16-3.94; P = .01; 1 year: RR, 2.29, 95% CI, 1.30 - 4.05; P=.003). Among patients with AMD and AF treated with warfarin, there was an increased risk of ocular complications (neovascular AMD: RR, 1.25; 95% CI, 1.14-1.38; P<.001; MH: RR, 1.86; 95% CI, 1.47-2.35; P<.001; VH: RR, 2.22; 95% CI, 1.51-3.26; P<.001) and need for intravitreal anti-VEGF therapy (RR, 1.34; 95% CI, 1.18-1.52; P<.001) over an extended 5-year period. There was no significant difference in the development of major systemic hemorrhagic events between the two cohorts over five years. CONCLUSIONS: Patients with non-neovascular AMD treated with warfarin were more likely to develop neovascular disease and require ocular intervention for hemorrhagic complications when compared to matched patients initiated on DOACs.

Assessment of Temporary Warfarin Reversal in Patients With Left Ventricular Assist Devices: the KVAD Study.

BACKGROUND: Patients with left ventricular assist devices (LVADs) require interruption of warfarin for invasive procedures, but parenteral bridging is associated with many complications. Four-factor prothrombin complex concentrate (4F-PCC) can temporarily restore hemostasis in patients undergoing anticoagulation with warfarin. OBJECTIVES: This pilot study evaluated the strategy of using variable-dose 4F-PCC to immediately and temporarily reverse warfarin before invasive procedures without holding warfarin in patients with LVADs. The duration of effect of 4F-PCC on factor levels and time to reestablish therapeutic anticoagulation post procedure were assessed. METHODS: Adult patients with LVADs and planned invasive procedures were enrolled from a single center. Warfarin was continued uninterrupted. The 4F-PCC dose administered immediately pre-procedure was based on study protocol. International normalized ratio (INR)- and vitamin K-dependent factor levels were collected before and during the 48 hours after 4F-PCC administration. The use of parenteral bridging, International Society for Thrombosis and Haemostasis major and clinically relevant nonmajor bleeding (CRNMB) and thromboembolic events at 7 and 30 days were collected. RESULTS: In 21 episodes of 4F-PCC reversal, median baseline INR was 2.7 (IQR 2.2-3.2). The median dosage of 4F-PCC administered was 1794 units (IQR 1536-2130). At 24 and 48 hours post 4F-PCC administration, median INRs were 1.8 (IQR 1.7-2.0) and 2.0 (IQR 1.9-2.4). Two patients required postoperative bridging. One patient experienced major bleeding within 72 hours, and 2 experienced CRNMB within 30 days. There were no thromboembolic events. Baseline and post 4F-PCC vitamin K-dependent factor levels corresponded with changes in INR values. The median time to achieve therapeutic INR post-procedure was 2.5 days (IQR, 1-4). CONCLUSION: Administration of 4F-PCC for temporary reversal of warfarin for invasive procedures in patients with LVADs allowed for continued warfarin dosing with minimal use of post-intervention bridging, limited bleeding and no thromboembolic events.

Relationship of Warfarin and Apixaban with Vascular Function in Patients with Atrial Fibrillation.

INTRODUCTION: Atrial fibrillation (AF) is associated with endothelial damage/dysfunction. Herein, we tested the hypothesis that brachial artery flow-mediated dilation (FMD) is superior in AF patients taking apixaban compared to warfarin. METHODS: AF patients on apixaban (n = 46; 67 [7] years; mean [standard deviation]; 15 women) and warfarin (n = 27; 73 [9] years (p < 0.01); 11 women) were recruited. Duplex Doppler ultrasound imaging was undertaken during baseline (2 min), cuff inflation (5 min), and following cuff deflation (3 min). FMD was defined as peak increase in brachial artery diameter following cuff deflation and analysed as percentage change in diameter, as a ratio of FMD, shear rate area under the curve (SRAUC; FMD-to-SRAUC), and using SRAUC as a covariate (FMDSR). RESULTS: Baseline artery diameter (4.96 [1.14] vs. 4.89 [0.88] mm), peak diameter (5.12 [1.17] vs. 5.14 [0.93] mm), and FMDSR (3.89 [3.62] vs. 4.80 [3.60] %) were not different between warfarin and apixaban (p > 0.05; analysis of covariance with age, CHA2DS2-VASc, years since AF diagnosis, number of diabetics, alcohol drinkers, and units of alcohol consumed per week as covariates). Stepwise multiple regression identified independent association of fibrillation, hypertension, and increased age with FMD. CONCLUSION: AF patients on warfarin and apixaban exhibit similar endothelium-dependent vasodilation. Increased blood pressure negatively impacts vasodilator capacity in AF patients.

Direct oral anticoagulants over warfarin at discharge associated with improved survival and patency in infra-geniculate bypasses with prosthetic conduits.

OBJECTIVE: There is no consensus on the optimal anticoagulant regimen following lower extremity bypass. Historically, warfarin has been utilized for prosthetic or compromised vein bypasses. Direct-acting oral anticoagulants (DOACs) are increasingly replacing warfarin in this context, but their efficacy in bypass preservation has not been well-studied. Recent studies have shown that DOACs may improve outcomes following bypasses; however, it is unclear if this is dependent upon type of bypass conduit. The goal of this study was to evaluate whether a difference exists between vein and prosthetic infra-geniculate bypasses outcomes based on the anticoagulant utilized on discharge, warfarin or DOAC. METHODS: The Vascular Quality Initiative infra-inguinal bypass database was queried for all patients who underwent an infra-geniculate bypass and were anticoagulation-naive at baseline but were discharged on either warfarin or DOACs. A survival analysis was performed for patients up to 1 year to determine whether the choice of discharge anticoagulation was associated with differences between those with vein vs prosthetic conduits in overall survival, primary patency, risk of amputation, or risk of major adverse limb events (MALE). A multivariable Cox proportional hazards analysis was performed to control for differences in baseline demographic factors between the groups. RESULTS: During the study period (2003-2020), 57,887 patients underwent infra-geniculate bypass. Of these, 3230 (5.5%) were anticoagulated on discharge. There was a similar distribution of anticoagulation between vein (n = 1659; 51.4%) and prosthetic conduits (n = 1571; 48.6%). Thirty-two percent were discharged on DOACs, and 68.0% were discharged on warfarin. For prosthetic conduits, being discharged on a DOAC was associated with improved outcomes on univariate and multivariable analyses revealing lower risk of overall mortality (hazard ratio [HR], 0.61; 95% confidence interval [CI], 0.41-0.93; P = .021), loss of primary patency (HR, 0.70; 95% CI, 0.55-0.89; P = .003), risk of amputation (HR, 0.71; 95% CI, 0.54-0.93; P = .013), and risk of MALE (HR, 0.80; 95% CI, 0.64-1.00; P = .048). Patients with a vein bypass had improved univariate outcomes for survival and primary patency; however, with multivariable analysis, there were no significant differences in outcomes between DOAC and warfarin. CONCLUSIONS: Anticoagulation-naive patients who underwent an infra-geniculate prosthetic bypass had higher rates of overall survival, bypass patency, amputation-free survival, and freedom from MALE when discharged on a DOAC compared with warfarin. Those with vein bypasses had similar outcomes regardless of the choice of anticoagulation.

Cardiac and renal outcomes of direct oral anticoagulants in patients with atrial fibrillation.

BACKGROUND: Oral anticoagulation therapy with warfarin or direct oral anticoagulants (DOACs) is the mainstay for stroke prevention in patients with non-valvular atrial fibrillation (AF). The DOACs might have a lower risk of declining renal function than warfarin. This study aimed to compare renal outcomes among rivaroxaban, edoxaban, dabigatran, and warfarin. METHOD: This cohort study identified 2203 adults with AF who started anticoagulation therapy between 1 July 2013 and 31 December 2020, in a clinical database at a single centre. Inverse probability of treatment weighting was adopted to balance baseline characteristics among four anticoagulants treatment groups. The primary outcome was a composite of cardiac and renal outcomes, involving a ≥30% decline in estimated glomerular filtration rate (eGFR), renal failure and cardiovascular death. RESULTS: After propensity score weighting, dabigatran was associated with significantly lower risks of a ≥30% decline in eGFR (hazard ratio [HR]: .69, 95% confidence interval [CI]: .497-.951, p = .0237), doubling of the serum creatinine level (HR: .49, 95% CI: .259-.927, p = .0282) and the cardiac and renal outcome composite (HR: .67, 95% CI: .485-.913, p = .0115) than warfarin. Rivaroxaban and edoxaban did not show significant protective effects on renal outcomes compared to warfarin. CONCLUSION: In this study, patients treated with dabigatran had significantly reduced risks of declining renal function and composite cardiac and renal events than those treated with warfarin. However, rivaroxaban and edoxaban were not associated with lower risks of any renal outcomes than warfarin. More studies are warranted to investigate and compare the impact of renal function between different DOACs in patients with AF.

Correlation between Metabolic Parameters and Warfarin Dose in Patients with Heart Valve Replacement of Different Genotypes.

Background: Warfarin has become the first choice for anticoagulation in patients who need lifelong anticoagulation due to its clinical efficacy and low price. However, the anticoagulant effect of warfarin is affected by many drugs, foods, etc. accompanied by a high risk of bleeding and embolism. The Vitamin K epoxide reductase complex 1 (VKORC1) and Cytochrome P450 2C9 (CYP2C9) genotypic variation can influence the therapeutic dose of warfarin. However, it is not clear whether there is a correlation between warfarin dose and liver function, kidney function and metabolic markers such as uric acid (UA) in patients with different genotypes. We performed a single-center retrospective cohort study to evaluate the factors affecting warfarin dose and to establish a dose conversion model for warfarin patients undergoing heart valve replacement. Methods: We studied 343 patients with a mechanical heart valve replacement, compared the doses of warfarin in patients with different warfarin-related genotypes (CYP2C9 and VKORC1), and analyzed the correlation between liver function, kidney function, UA and other metabolic markers and warfarin dose in patients with different genotypes following heart valve replacement. Results: Genotype analysis showed that 72.01% of patients had CYP2C9*1/*1 and VKORC1 mutant AA genotypes. Univariate regression analysis revealed that the warfarin maintenance dose was significantly correlated with gender, age, body surface area (BSA), UA and genotype. There was no correlation with liver or kidney function. Multiple linear regression analysis showed that BSA, genotype and UA were the independent factors influencing warfarin dose. Conclusions: There is a significant correlation between UA content and warfarin dose in patients with heart valve replacement genotypes CYP2C9*1/*1/VKORC1(GA+GG), CYP2C9*1/*1/VKORC1AA and CYP2C9*1/*1/VKORC1AA.

Outcomes of Warfarin Home INR Monitoring vs Office-Based Monitoring: a Retrospective Claims-Based Analysis.

BACKGROUND: Home INR testing (patient self-testing) is feasible and effective for warfarin patients but little is known about real-world differences in outcomes for patients using PST versus laboratory-based INR monitoring. OBJECTIVE: To compare the safety/efficacy of patient self-testing of real-world warfarin therapy versus office/lab-based monitoring of therapy. DESIGN/SETTING/PARTICIPANTS/EXPOSURE: A retrospective claims-based analysis of warfarin patients enrolled in the MarketScan® Commercial Claims and Encounters and Medicare databases between January 1, 2013, and March 30, 2020. Stratification was based on INR testing method: patient self-testing versus testing at physicians' offices/local laboratory. The probability of adverse events in each cohort was determined after adjusting for demographic and baseline clinical characteristics using a repeated measures analysis. MAIN MEASURES: Rates of all adverse events: deep venous thrombosis, pulmonary embolism, bleeding, and stroke. A secondary outcome of interest was emergency department visits. KEY RESULTS: A total of 37,837 patients were included in the analysis: 1592 patients in the patient self-testing group and 36,245 in the office-based therapy group. After adjusting for demographic and baseline clinical characteristics, patients in the office-based group had statistically significantly higher rates of all adverse events (incidence rate ratio [IRR]=2.07, 95% CI [1.82, 2.36]), and specific adverse events including thromboembolism (IRR=4.38, 95% CI [3.29, 5.84]), major bleed (IRR=1.45, 95% CI [1.28, 1.64]), and stroke (IRR=1.30, 95% CI [1.05, 1.61]) than patients in the patient self-testing group. Office-based patients also had a statistically significant higher rate of emergency department visits than patient self-testing patients (IRR = 1.65, 95% CI [1.47, 1.84]). CONCLUSIONS/RELEVANCE: This analysis of real-world claims data shows lower rates of stroke, thromboembolism, and major bleeding, as well as fewer emergency department visits, with patient self-testing compared to office-based/lab INR monitoring. Our finding that PST is safe and effective among current users suggests that more patients may benefit from its use.

Anticoagulation in Patients with Chronic Kidney Disease.

BACKGROUND: Both atrial fibrillation and venous thromboembolism (VTE) are highly prevalent among patients with chronic kidney disease (CKD). Until recently, warfarin was the most commonly prescribed oral anticoagulant. Direct oral anticoagulants (DOACs) have important advantages and have been shown to be noninferior to warfarin with respect to stroke prevention or recurrent VTE in the general population, with lower bleeding rates. This review article will provide available evidence on the use of DOACs in patients with CKD. SUMMARY: In post hoc analyses of major randomized studies with DOACs for stroke prevention in atrial fibrillation, in the subgroup of participants with moderate CKD, defined as a creatinine clearance (CrCl) of 30-50 mL/min, dabigatran 150 mg and apixaban were associated with lower rates of stroke and systemic embolism, whereas apixaban and edoxaban were associated with lower bleeding and mortality rates, compared with warfarin. In retrospective observational studies in patients with advanced CKD (defined as a CrCl <30 mL/min) and atrial fibrillation, DOACs had similar efficacy with warfarin with numerically lower bleeding rates. All agents warrant dose adjustment in moderate-to-severe CKD. In patients on maintenance dialysis, the VALKYRIE trial, which was designed initially to study the effect of vitamin K on vascular calcification progression, established superiority for rivaroxaban compared with a vitamin K antagonist (VKA) in the extension phase. Two other clinical trials using apixaban (AXADIA and RENAL-AF) in this population were inconclusive due to recruitment challenges and low event rates. In post hoc analyses of randomized studies with DOACs in patients with VTE, in the subgroup of participants with moderate CKD at baseline, edoxaban was associated with lower rates of recurrent VTE, whereas rivaroxaban and dabigatran were associated with lower and higher bleeding rates, respectively, as compared to warfarin. KEY MESSAGES: DOACs have revolutionized the management of atrial fibrillation and VTE, and they should be preferred over warfarin in patients with moderate-to-severe CKD with appropriate dose adjustment. Therapeutic drug monitoring with a valid technique may be considered to guide clinical management in individualized cases. Current evidence questions the need for oral anticoagulation in patients on maintenance dialysis with atrial fibrillation as both DOACs and VKAs are associated with high rates of major bleeding.

Effectiveness and Safety of Non-Vitamin K Oral Anticoagulants versus Warfarin in Patients with Atrial Fibrillation and Previous Stroke: A Systematic Review and Meta-Analysis.

INTRODUCTION: Current evidence regarding the clinical outcomes of non-vitamin K oral anticoagulants (NOACs) versus warfarin in patients with atrial fibrillation (AF) and previous stroke is inconclusive, especially in patients with previous intracranial haemorrhage (ICrH). We aim to undertake a systematic review and meta-analysis assessing the effectiveness and safety of NOACs versus warfarin in AF patients with a history of stroke. METHODS: We searched studies published up to December 10, 2022, on PubMed, Medline, Embase, and Cochrane Central Register of Controlled Trials. Studies on adults with AF and previous ischaemic stroke (IS) or IrCH receiving either NOACs or warfarin and capturing outcome events (thromboembolic events, ICrH, and all-cause mortality) were eligible for inclusion. RESULTS: Six randomized controlled trials (RCTs) (including 19,489 patients with previous IS) and fifteen observational studies (including 132,575 patients with previous IS and 13,068 patients with previous ICrH) were included. RCT data showed that compared with warfarin, NOACs were associated with a significant reduction in thromboembolic events (odds ratio [OR]: 0.85, 95% confidence interval [CI]: 0.75-0.96), ICrH (OR: 0.57, 95% CI: 0.36-0.90), and all-cause mortality (OR: 0.88, 95% CI: 0.80-0.98). In analysing observational studies, similar results were retrieved. Moreover, patients with previous ICrH had a lower OR on thromboembolic events than those with IS (OR: 0.66, 95% CI: 0.46-0.95 vs. OR: 0.80, 95% CI: 0.70-0.93) in the comparison between NOACs and warfarin. CONCLUSIONS: Observational data showed that in AF patients with previous stroke, NOACs showed better clinical performance compared to warfarin and the benefits of NOACs were more pronounced in patients with previous IrCH versus those with IS. RCT data also showed NOACs are superior to warfarin. However, current RCTs only included AF patients who survived an IS, and further large RCTs focused on patients with previous ICrH are warranted.

Pharmacogenetic guided versus standard warfarin dosing for routine clinical care with its pharmacoeconomic impact: a randomized controlled clinical trial.

BACKGROUND: Empirical use of pharmacogenetic test(PGT) is advocated for many drugs, and resource-rich setting hospitals are using the same commonly. The clinical translation of pharmacogenetic tests in terms of cost and clinical utility is yet to be examined in hospitals of low middle income countries (LMICs). AIM: The present study assessed the clinical utility of PGT by comparing the pharmacogenetically(PGT) guided- versus standard of care(SOC)- warfarin therapy, including the health economics of the two warfarin therapies. METHODS: An open-label, randomized, controlled clinical trial recruited warfarin-receiving patients in pharmacogenetically(PGT) guided- versus standard of care(SOC)- study arms. Pharmacogenetic analysis of CYP2C9*2(rs1799853), CYP2C9*3(rs1057910) and VKORC1(rs9923231) was performed for patients recruited to the PGT-guided arm. PT(Prothrombin Time)-INR(international normalized ratio) testing and dose titrations were allowed as per routine clinical practice. The primary endpoint was the percent time spent in the therapeutic INR range(TTR) during the 90-day observation period. Secondary endpoints were time to reach therapeutic INR(TRT), the proportion of adverse events, and economic comparison between two modes of therapy in a Markov model built for the commonest warfarin indication- atrial fibrillation. RESULTS: The study enrolled 168 patients, 84 in each arm. Per-protocol analysis showed a significantly high median time spent in therapeutic INR in the genotype-guided arm(42.85%; CI 21.4-66.75) as compared to the SOC arm(8.8%; CI 0-27.2)(p < 0.00001). The TRT was less in the PG-guided warfarin dosing group than the standard-of-care dosing warfarin group (17.85 vs. 33.92 days) (p = 0.002). Bleeding and thromboembolic events were similar in the two study groups. Lifetime expenditure was ₹1,26,830 in the PGT arm compared to ₹1,17,907 in the SOC arm. The QALY gain did not differ in the two groups(3.9 vs. 3.65). Compared to SOC, the incremental cost-utility ratio was ₹35,962 per QALY gain with PGT test opting. In deterministic and probabilistic sensitivity analysis, the base case results were found to be insensitive to the variation in model parameters. In the cost-effectiveness-acceptability curve analysis, a 90% probability of cost-effectiveness was reached at a willingness-to-pay(WTP) of ₹ 71,630 well below one time GDP threshold of WTP used. CONCLUSION: Clinical efficacy and the cost-effectiveness of the warfarin pharmacogenetic test suggest its routine use as a point of care investigation for patient care in LMICs.

Association between polymorphisms of the VKORC1 and CYP2C9 genes and warfarin maintenance dose in Peruvian patients.

AIMS: The aim of this study was to investigate the association between VKORC1 and CYP2C9 genes polymorphisms and the maintenance dose of warfarin in Peruvian patients. METHODS: An observational study was conducted on outpatients from the Hospital Grau ESSALUD in Lima, Peru. The participants were selected using nonprobabilistic convenience sampling. Inclusion criteria required patients to have been on anticoagulation therapy for >3 months, maintain stable doses of warfarin (consistent dose for at least 3 outpatient visits), and maintain an international normalized ratio within the therapeutic range of 2.5-3.5. DNA samples were obtained from peripheral blood for gene analysis. RESULTS: Seventy patients (mean age of 69.6 ± 13.4 years, 45.7% female) were included in the study. The average weekly warfarin dose was 31.6 ± 15.2 mg. The genotypic frequencies of VKORC1 were as follows: 7.1% (95% confidence interval, 2.4-15.9) for AA; 44.3% (32.4-56.7) for GA; and 48.6% (36.4-60.8) for GG. No deviation from the Hardy-Weinberg equilibrium was observed in the variants studied (P = .56). The mean weekly warfarin doses for AA, GA and GG genotypes were 16.5 ± 2.9, 26.5 ± 9.5 and 37.9 ± 17.1 mg, respectively (P < .001). The genotypic frequencies of CYP2C9 were as follows: 82.8% (72.0-90.8) for CC (*1/*1); 4.3% (1.0-12.0) for CT (*1/*2); and 12.9% (6.1-23.0) for TT (*2/*2). We did not find a significant association between the CYP2C9 gene polymorphism and the dose of warfarin. CONCLUSIONS: The AA genotype of the VKORC1 gene was associated with a lower maintenance dose of warfarin in Peruvian patients.