Direct-acting Oral Anticoagulants Research Articles

Analysis of the therapeutic effect and application of anticoagulant drugs

As the global population ages, the incidence of cardiovascular disease, stroke, and other diseases associated with thrombosis is also increasing, resulting in a great need for effective anticoagulant treatments. The purpose of this research is to summarize the development of anticoagulant drugs to date, including their drug types, version iterations, mechanisms of action, as well as current challenges and future development directions of anticoagulant drugs. The research will first review traditional anticoagulants, such as vitamin K antagonists and heparins, and discuss in detail their effects, advantages, and limitations. Next, it will give a detailed description of new anticoagulants, such as direct acting oral anticoagulants (DOACs), and analyse their advantages over traditional anticoagulants in terms of safety and efficacy. Finally, it will propose the strategy of individualized therapy for specific population and the combination therapy of anticoagulant therapy and other drugs, and look forward to the development of new anticoagulant drugs in the future. The application of anticoagulant drugs in medicine has a wide range of clinical significance. With the continuous deepening of research, new therapeutic strategies and drugs are constantly being developed and improved, aiming at providing more safe and effective anticoagulant therapy.

Adoption of new medicines in primary care: A comparison between the uptake of new oral anticoagulants and diabetes medicines.

To gain insight in the uptake and practice variation in the prescription of 2 new medicine groups for common conditions in primary care (direct-acting oral anticoagulants [DOACs] and incretin-based therapies) from introduction, around 2007, to 2019 and the correlation between the adoption of those medicines in primary care. Prescription data from general practices in the Dutch Nivel Primary Care Database from 2007 to 2019 were used. The percentage of patients with prescriptions for DOACs of all patients with prescriptions for DOACs and vitamin K antagonists was calculated per practice per year, as was the percentage of patients prescribed incretin-based therapies as a proportion of all patients with diabetes medication. Multilevel models were used to estimate practice variation for DOACs and incretin-based therapies, expressed as intraclass correlation coefficients. Linear regression analysis was used to study the association between the prescription of DOACs and incretin-based therapies. Per year, 46-424 general practices and 179 933-1654 376 patients were included. In 2019, the mean percentage of patients per practice using DOACs or incretin-based therapies was 54.9 and 9.7%, respectively. The intraclass correlation coefficient decreased from 0.75 to 0.024 for DOACs and from 0.33 to 0.074 for incretin-based medicines during the study period. No clear correlation was found between the prescription of DOACs and incretin-based therapies. DOACs and incretin-based therapies have different adoption profiles and practice variation is large, especially in the years before these medicines were introduced in guidelines. Early adopters of both medicine classes differ.

Diagnosis and Therapy of Visceral Vein Thrombosis: An Update Based on the Revised AWMF S2k Guideline.

Splanchnic or visceral vein thromboses (VVTs) are atypical thrombotic entities and include thrombosis of the portal vein, hepatic veins (Budd-Chiari syndrome), mesenteric veins, and splenic vein. All VVTs have in common high 30-day mortality up to 20% and it seems to be difficult to diagnose VVT early because of their rarity and their wide spectrum of unspecific symptoms. VVTs are often associated with myeloproliferative neoplasia, thrombophilia, and liver cirrhosis. VVT is primarily diagnosed by sonography and/or computed tomography. In contrast to venous thromboembolism, D-dimer testing is neither established nor helpful. Anticoagulation is the first-line therapy in patients with stable circulation and no evidence of organ complications. Anticoagulation improves significantly recanalization rates and stops the progress of thrombosis. Low-molecular-weight heparin, vitamin K antagonists, as well as direct-acting oral anticoagulants are possible anticoagulants, but it is noteworthy to be aware that all recommendations supporting the off-label use of anticoagulants are based on poor evidence and consist predominantly of case series, observational studies, or studies with small case numbers. When choosing a suitable anticoagulation, the individual risk of bleeding and thrombosis must be weighted very carefully. In cases of bleeding, bowel infarction, or other complications, the optimal therapy should be determined on a case-by-case basis by an experienced multidisciplinary team involving a surgeon. Besides anticoagulation, there are therapeutic options including thrombectomy, balloon angioplasty, stenting, transjugular placement of an intrahepatic portosystemic shunt, liver transplantation, and ischemic bowel resection. This article gives an overview of current diagnostic and therapeutic strategies.

Thromboprophylaxis strategies in patients undergoing endovenous thermal ablation: a UK survey

Introduction: It remains unclear whether patients undergoing endovenous thermal ablation (EVTA) for superficial venous incompetence (SVI) should receive pharmacological thromboprophylaxis. A survey was conducted to assess current thromboprophylaxis practices across the UK in patients undergoing EVTA for SVI. Methods: To examine the thromboprophylaxis practices of clinicians performing EVTA for SVI in the UK, an online survey was developed using the Qualtrics online survey tool. The survey link was circulated via email to members of the multidisciplinary collaborative Vascular and Endovascular Research Network (VERN) and promoted through social media. The primary focus of the survey was to gather information regarding venous thromboembolism (VTE) prophylaxis during EVTA for SVI. Results: A total of 32 vascular surgeons and one vascular nurse specialist based in the UK participated in the survey. All respondents reported routine prescription of compression therapy in the immediate postoperative period. Of all the respondents, 67% (n=22) reported routine prescription of pharmacological thromboprophylaxis during the peri-procedural period. Extended prophylaxis was routinely offered by 15% (n=5) of all respondents. Among those who provided extended prophylaxis, the majority (80%, n=4) used low molecular weight heparin (LMWH), while 20% (n=1) opted for a direct-acting oral anticoagulant (DOAC). Conclusion: The findings from this survey indicate that a significant proportion of patients undergoing EVTA for SVI routinely receive pharmacological thromboprophylaxis, with a single perioperative dose of LMWH being the prevailing practice. However, there is a notable lack of robust high-quality evidence to substantiate this practice. Grade A evidence is required to assess the potential benefit of pharmacological thromboprophylaxis in the context of EVTA to guide the development of clinically relevant guidelines. Should pharmacological thromboprophylaxis prove to offer no additional benefit for this specific patient population, this could result in cost savings for the NHS and enable patients to avoid unwanted side effects associated with anticoagulation therapy.

Association of Depression and Adherence to Oral Anticoagulation in Patients With Atrial Fibrillation.

Adherence to oral anticoagulation is essential for stroke prevention in atrial fibrillation (AF). Depression has been associated with decreased adherence to medications in multiple disease states and in AF is further associated with increased risk of stroke. We hypothesized that individuals with depression and AF have decreased adherence to anticoagulation than those without depression. We used administrative claims data to identify individuals with AF initiating anticoagulation with direct-acting oral anticoagulants (DOACs) or warfarin between 2013 and 2019. We quantified adherence using proportion of days covered, categorized as limited (proportion of days covered, <80%), adequate (proportion of days covered, ≥80% to <90%), or optimal (proportion of days covered, ≥90%). We related depression to 12-month adherence to anticoagulation in logistic regression models, adjusting for demographics, medical and psychiatric comorbidities, household income, educational attainment, and insurance type. As a secondary analysis, we determined the association of depression to adherence for each DOAC agent. We identified 101 041 individuals (aged 74.5±8.9 years; 50.6% women; 29.5% race or ethnicity other than White, including Asian or Black race and Hispanic ethnicity) who initiated either DOACs or warfarin. The odds of adequate adherence to DOACs was 11% (95% CI, 0.85-0.93), and the odds of optimal adherence was 12% (95% CI, 0.83-0.91) less in individuals with depression than those without. Depression was not associated with adherence to warfarin. We identified an association between depression and decreased adherence to DOACs but not warfarin in individuals with AF. Recognizing depression in AF may guide interventions to improve anticoagulation adherence and reduce stroke risk.

Evidence of the association between increased use of direct oral anticoagulants and a reduction in the rate of atrial fibrillation-related stroke and major bleeding at the population level (2012–2019)

BackgroundThe introduction of direct-acting oral anticoagulants (DOACs) has shown to decrease atrial fibrillation (AF)-related stroke and bleeding rates in clinical studies, but there is no certain evidence about their effects at the population level. Our aim was to assess changes in AF-related stroke and major bleeding rates between 2012 and 2019 in Andalusia (Spain), and the association between DOACs use and events rates at the population level. MethodsAll patients with an AF diagnosis from 2012 to 2019 were identified using the Andalusian Health Population Base, that provides clinical information on all Andalusian people. Annual ischemic and hemorrhagic stroke, major bleeding rates, and used antithrombotic treatments were determined. Marginal hazard ratios (HR) were calculated for each treatment. ResultsA total of 95,085 patients with an AF diagnosis were identified. Mean age was 76.1±10.2 years (49.7% women). An increase in the use of DOACs was observed throughout the study period in both males and females (p<0.001). The annual rate of ischemic stroke decreased by one third, while that of hemorrhagic stroke and major bleeding decreased 2–3-fold from 2012 to 2019. Marginal HR was lower than 0.50 for DOACs compared to VKA for all ischemic or hemorrhagic events. ConclusionsIn this contemporary population-based study using clinical and administrative databases in Andalusia, a significant reduction in the incidence of AF-related ischemic and hemorrhagic stroke and major bleeding was observed between 2012 and 2019. The increased use of DOACs seems to be associated with this reduction.

Development and validation of the DOAC Score: a novel bleeding risk prediction tool for patients with atrial fibrillation

Abstract Background Clinicians and patients must balance the ischemic benefits and bleeding risks when deciding to anticoagulate patients with atrial fibrillation (AF). Current clinical decision tools for assessing bleeding risk have limited performance and were developed for individuals anticoagulated with warfarin. Purpose This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with AF taking direct-acting oral anticoagulants (DOACs). Methods Among individuals taking dabigatran 150mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial, a risk score was developed to determine the probability for bleeding, based on covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. We then refined the model in the GARFIELD-AF registry, with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACS, the risk prediction model was validated in the COMBINE-AF pooled clinical trial cohort and the RAMQ administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared to the HAS-BLED score. Results Of the 5684 patients in RE-LY, 386 experienced a major bleeding event, within a median follow-up of 1.74-years. The prediction model was well-calibrated (goodness-of-fit P = 0.57) and had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping. The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, non-steroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI: 38.9%-59.3%, P&amp;lt;0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C Statistic: 0.73 vs 0.60, P for difference &amp;lt;0.001) and among 12,296 individuals in GARFIELD-AF (C statistic: 0.71 vs 0.66, P for Difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25,586 individuals in COMBINE-AF (C statistic: 0.67 vs 0.63, P for Difference &amp;lt;0.001) and 11,945 individuals in RAMQ (C statistic: 0.65 vs 0.58, P for Difference &amp;lt;0.001). Conclusion In individuals with AF on DOAC therapy, the DOAC Score can help stratify patients based on expected bleeding risk.

Abstract 14451: Switching From Warfarin to Direct Oral Anticoagulants (DOACs) in Medicine Clinic at a Safety Net Hospital in New York City: A Quality Improvement Project

Introduction: Many patients are still using warfarin for thromboembolic prevention, even though Direct-Acting Oral Anticoagulants (DOACs) have replaced it in most indications to decrease the need for frequent dose adjustments and minimize drug interactions. Methods: This study is a clinic patient-based observational quality improvement project to review warfarin use in adult patients following at the anticoagulation clinic at Metropolitan Hospital. Electronic medical records were screened, and TTR was calculated over 3 months. STATA was used for statistical analysis, including Histograms, Skewness-Kurtosis tests for normality, student-T tests for continuous variables, and χ2 tests for categorical variables. The P-value of less than 0.05 was considered statically significant. Results: A total of 45 patients were included; the mean age was 61, of whom 23 (51.1%) were males. The comorbidities observed were hypertension (HTN), diabetes mellitus (DM), chronic obstructive pulmonary disease (COPD), and obesity. The time in therapeutic range (TTR) was less than 65% in 22 patients (48.9%). Warfarin was indicated in 28 patients (62.2%) and not indicated in 17 patients (37.8%), out of which 6 patients (36.3%) agreed to switch to direct oral anticoagulants (DOACs) (Figure 1). Conclusions: Our project revealed a significant number of patients are still using warfarin despite being suitable for DOACs. 60% prefer warfarin due to perceived safety with frequent clinic visits. Socioeconomic status affects the transition. The PINNACLE Study identified practice and provider variations, Practices with high-volume clinics, more electrophysiologists, and those located in the western region are more likely to switch to DOACs. Based on our findings, we recommend the following: - Physicians should engage in shared decision-making with patients on warfarin use. - Physicians may need to discuss the available DOACs options with insurance companies due to coverage limitations.

Oral Anticoagulant (OAC) Use Among Medicare Patients Newly Diagnosed with Venous Thromboembolism (VTE): Factors Associated with Treatment Status

Introduction Clinical guidelines recommend initial treatment with OACs, such as direct-acting oral anticoagulants (DOACs; apixaban, dabigatran, edoxaban, rivaroxaban) or warfarin, for at least 3 months after an initial venous thromboembolism (VTE) event. Early OAC use is associated with improved clinical outcomes and helps prevent VTE recurrence. Purpose To estimate the proportion of Medicare beneficiaries newly diagnosed with VTE with and without OAC treatment within the month from first VTE and identify factors associated with being untreated in that period. Additionally, to identify factors associated with treatment with DOACs or warfarin among OAC-treated patients. Methods Data from 1/1/2014-12/31/2019 of Medicare beneficiaries aged ≥65 years with a new diagnosis of VTE in the inpatient or ambulatory (including emergency room [ER]) setting from 1/1/2015 to 12/31/2019 were included. Additional eligibility criteria included continuous Medicare Parts A, B and D enrollment ≥12 months before and ≥30 days after first VTE diagnosis (index VTE), no diagnosis for atrial fibrillation, inferior vena cava filter, pregnancy or cancer, and no OAC treatment prior to index VTE. VTE patients with ≥1 outpatient pharmacy claims for a DOAC or warfarin within 30 days from index VTE were considered OAC-treated; otherwise, they were classified as untreated. Patients in the OAC-treated cohort were further classified into the DOAC or warfarin subgroups based on the first OAC treatment observed from index VTE (index OAC). Factors associated with being untreated with OACs (vs. treated) and with receiving treatment with DOACs (vs. warfarin) were assessed using multivariable logistic regressions. Results A total of 169,928 patients (49.7% OAC-treated; 50.3% untreated) were identified. In the OAC-treated cohort, 62,528 (74.0%) had DOACs (mainly apixaban [51.9%] and rivaroxaban [46.9%]), and 29,324 (26.0%) warfarin as index OAC. Within the OAC-treated and untreated cohorts respectively, mean age was 76.2 and 77.3 years, 62.9% and 66.4% were female, 82.6% and 75.4% were Non-Hispanic White, mean CCI score was 2.0 and 3.0, 51.8% and 70.3% had DVT only, and 48.2% and 29.7% had PE. Factors associated with being untreated with OACs (odds ratio; 95% confidence interval) included Hispanic ethnicity (vs. White) (1.35; 1.29-1.42), congestive heart failure (1.44; 1.39-1.48), cerebrovascular disease (1.36; 1.32-1.39), anemia (1.25; 1.22-1.28), and peripheral vascular disease (1.22; 1.19-1.25). Having part D low-income subsidy was also associated with being untreated with OACs (1.14; 1.07, 1.20). Index VTE diagnosis setting being ER (vs. outpatient) (0.38; 0.36-0.39) and pulmonary embolism (vs. DVT) (0.45; 0.44-0.46) were associated with increased odds of being treated with OAC, as was being diagnosed by a radiologist (0.62; 0.60-0.64), emergency medicine physician (0.52; 0.49-0.56) or hematologist (0.56; 0.50-0.63) (vs. primary care) ( Figure 1). Among the OAC-treated cohort, factors associated with being treated with DOACs vs. warfarin included diagnosis in more recent years, VTE in ER setting (1.22; 1.15-1.30). VTE in inpatient setting (0.74; 0.70-0.78) and renal disease (0.73; 0.70-0.76) were associated with increased odds of being treated with warfarin, as were Northeast (0.79; 0.76-0.83), Midwest (0.52; 0.50-0.54), and West US census regions (0.56; 0.53-0.59), respectively ( Figure 2). Conclusions In this study of Medicare patients, nearly half of the patients with ICD codes for VTE were not treated with OAC in the first month from initial diagnosis. Among OAC-treated patients, a higher proportion of patients were treated with DOAC vs. warfarin, consistent with more recent guideline recommendation. Factors associated with being untreated might reflect challenges associated with VTE management among disadvantaged populations and in the presence of certain comorbidities.

Anticoagulant therapy with apixaban based on a pharmacogenetic approach: a course to safety

For the past 60 years, vitamin K antagonists (VKAs) have been the main drugs used for long-term oral anticoagulant therapy. Because of the significant limitations of AVCs, direct-acting oral anticoagulants (DOAKs) have been developed over the past decade. DOAKs have a predictable pharmacokinetic profile and lack the disadvantages of vitamin K antagonists. Apixaban is an oral direct-acting factor Xa inhibitor used for the prevention of thromboembolic complications in patients with non-valvular atrial fibrillation (AF) and deep vein thrombosis. Despite the use of recommended dosages, some patients may still experience bleeding or lack the desired anticoagulant effect. With this in mind, it is critical to explore new uses for direct oral anticoagulants and to predict their dosage when used in monotherapy or in combination with other drugs. In addition, recent studies have documented individual variability in plasma POAC levels. DOAC pharmacogenetics is a relatively new area of research. There is a need to understand the role of pharmacogenetics in adapting anticoagulant therapy according to a patient’s genetic characteristics. In this scientific review of current data, we detail the pharmacokinetics and pharmacogenetics of apixaban as well as new data concerning the clinical characteristics that predetermine the necessary dosage and risk of adverse drug reactions (ADRs). Indeed, the results obtained to date from basic and clinical studies certainly indicate an undeniable influence of genomic changes on the pharmacokinetics of POACs.

Comparison of direct oral anticoagulants versus low-molecular-weight heparin in primary and metastatic brain cancers: a meta-analysis and systematic review

BackgroundThe safety and efficacy of direct-acting oral anticoagulants (DOACs) for therapeutic anticoagulation in the setting of primary or metastatic brain cancer is not known. ObjectivesTo conduct a meta-analysis and systematic review of studies that compare the risk of intracranial hemorrhage (ICH) in patients with brain cancer treated with DOACs vs low-molecular-weight heparin (LMWH). MethodsA literature search was conducted using PubMed, EMBASE, and Cochrane databases. Summary statistics were obtained by calculating the risk ratio (RR), and heterogeneity across studies was estimated using the I2 statistic. A total of 10 retrospective studies (n = 1638) met criteria for inclusion. The primary endpoint was the pooled RR for ICH in patients with brain tumors receiving anticoagulation with DOACs compared with those receiving LMWH. Secondary analyses included the risk of fatal ICH in each subgroup. ResultsThe pooled RR for ICH in patients receiving DOACs vs those receiving LMWH was 0.65 (95% CI, 0.36-1.17; P = .15; I2 = 50%). In studies evaluating primary brain cancer, there was a reduction in risk of ICH with DOACs (RR, 0.35; 95% CI, 0.18-0.69; P = .003; I2 = 0%). In patients with metastatic brain cancer, there was no difference in the risk of ICH with the type of anticoagulation (RR, 1.05; 95% CI, 0.71-1.56; P = .80; I2 = 0%). The overall risk of fatal ICH was not different between anticoagulants. ConclusionThe risk of ICH in patients with brain cancer receiving therapeutic anticoagulation varies by anticoagulation agent and diagnosis of primary or metastatic disease.

Clinical outcomes for patients on antiplatelet and anticoagulants in thoracoabdominal trauma

IntroductionTrauma outcomes can be greatly affected by antiplatelet and anticoagulant (AP/AC) use. The goal of this study was to compare outcomes in trauma patients on AP/AC undergoing emergent surgery for thoracoabdominal trauma at 35 level 1 and 2 trauma centers from 2014 to 2021. MethodsThis was a retrospective cohort study of 2460 adult patients with a chest, abdomen, or pelvis abbreviated injury score (AIS) of 2 or more who underwent surgery within 24 h of admission. These patients were segregated into four main cohorts based on antiplatelet/anticoagulation use: those not on AP/AC, those taking direct-acting oral anticoagulants (DOACs), those taking clopidogrel, and those taking warfarin. Patients were excluded if they had surgery >24 h after presentation, were dead on arrival, or had any other body system AIS score of 3 or higher. ResultsThe mean injury severity score (ISS) in all four groups ranged from 16.3 to 18.6 (p = 0.834) with a mean time to operating room from 208 to 478 min (p < 0.001). Laparotomy was performed in 60 to 71 % (p > 0.01) of patients, regardless of AP/AC status, and thoracic procedures were performed in 3.1 to 9.3 % (p = 0.42) of patients. In-hospital mortality and hospice rates were highest in the clopidogrel group at 21.9 %, followed by warfarin at 13 %, DOACs at 15 %, and no AP/AC at 7.63 % (p = 0.008). Serious complications occurred in 61 % of patients on warfarin, 50 % of those on DOACs, and 44 % of those on clopidogrel. All of these groups demonstrated significantly higher complication rates than patients in the no AP/AC control group at 25 % (p < 0.001). Total transfusion of packed red blood cells and fresh frozen plasma did not differ significantly between the groups; however, 24-h platelet transfusion did. Patients on clopidogrel received 14 packs of platelets, while those on warfarin and DOACs received 8 and 13 packs respectively (p = 0.011). Patients on warfarin had the longest hospital length of stay (LOS) at 13 days and ICU LOS at 9 days, compared to those on DOACs (8 and 4), those on clopidogrel (7 and 3), and those not taking AC/AP (7 and 4) (hospital LOS p = 0.03, ICU LOS p = 0.019). Those on AC/AP were also noted to be significantly older than those on neither, with those taking these medications averaging out to be approximately 69 years old and those not on these medications averaging 37 years old (p < 0.001). ConclusionThere was significantly higher mortality in patients on clopidogrel and increased length of stay and risk of serious complications in patients taking DOACs and warfarin. In patients on AP/AC there was also a significantly longer time to surgery than in those not taking either. Given these associations trauma surgeons should consider intervening sooner on patients taking AP/AC on admission, as the delay to intervention may contribute to the risks for trauma patients and result in worse outcomes as well as higher rates of mortality.

Real-world evidence that among atrial fibrillation patients warfarin is associated with reduced nonelective admissions compared with those on DOACs.

Randomized trials show inconsistent estimates on risks of direct-acting oral anticoagulants (DOACs) versus warfarin in bleeding and mortality for atrial fibrillation (AF) patients. Trials are confounded by additional DOAC adherence support, while warfarin has a low time in therapeutic range. Few real-world studies compared emergency hospitalization risk between DOAC and warfarin users in AF. This study aimed to determine emergency hospitalization risk for AF patients on DOACs or warfarin in real-world settings. A tapered-matched real-world cohort extracted data from 412 English general practices' primary care records linked with emergency department (ED) and hospitalization data from the ECLIPSE database. AF patients with new DOAC or warfarin prescriptions were included. The primary outcome was all-cause ED attendance; the secondary outcomes were ED re-attendance, nonelective hospitalization, and rehospitalization within 12 months. Weighted Cox regression estimated relative risk difference. 39 201 DOAC patients were matched with 13 145 warfarin patients. DOAC patients had a 25% higher likelihood of attending ED (odds ratio 1.25; 95% confidence interval [CI] 1.01-1.55). DOAC use also associated with higher ED re-attendance, nonelective hospitalization, and rehospitalization within 12 months: 1.41 (95% CI 1.00-1.98), 1.26 (1.00-1.57), and 1.54 (1.01-2.34), respectively, with p-values < .05. DOACs for AF thromboprophylaxis are associated with the increased risk of ED attendance, recurrent hospitalization, and numerical rise in ED re-attendance and first nonelective hospitalization compared to warfarin. However, these real-world data cannot establish if this difference results from medication adherence, lack of regular warfarin clinic monitoring, unmeasured confounders, or fundamental agent efficacy disparities.

Development and Validation of the DOAC Score: A Novel Bleeding Risk Prediction Tool for Patients With Atrial Fibrillation on Direct-Acting Oral Anticoagulants.

Current clinical decision tools for assessing bleeding risk in individuals with atrial fibrillation (AF) have limited performance and were developed for individuals treated with warfarin. This study develops and validates a clinical risk score to personalize estimates of bleeding risk for individuals with atrial fibrillation taking direct-acting oral anticoagulants (DOACs). Among individuals taking dabigatran 150 mg twice per day from 44 countries and 951 centers in this secondary analysis of the RE-LY trial (Randomized Evaluation of Long-Term Anticoagulation Therapy), a risk score was developed to determine the comparative risk for bleeding on the basis of covariates derived in a Cox proportional hazards model. The risk prediction model was internally validated with bootstrapping. The model was then further developed in the GARFIELD-AF registry (Global Anticoagulant Registry in the Field-Atrial Fibrillation), with individuals taking dabigatran, edoxaban, rivaroxaban, and apixaban. To determine generalizability in external cohorts and among individuals on different DOACs, the risk prediction model was validated in the COMBINE-AF (A Collaboration Between Multiple Institutions to Better Investigate Non-Vitamin K Antagonist Oral Anticoagulant Use in Atrial Fibrillation) pooled clinical trial cohort and the Quebec Régie de l'Assurance Maladie du Québec and Med-Echo Administrative Databases (RAMQ) administrative database. The primary outcome was major bleeding. The risk score, termed the DOAC Score, was compared with the HAS-BLED score. Of the 5684 patients in RE-LY, 386 (6.8%) experienced a major bleeding event, within a median follow-up of 1.74 years. The prediction model had an optimism-corrected C statistic of 0.73 after internal validation with bootstrapping and was well-calibrated based on visual inspection of calibration plots (goodness-of-fit P=0.57). The DOAC Score assigned points for age, creatinine clearance/glomerular filtration rate, underweight status, stroke/transient ischemic attack/embolism history, diabetes, hypertension, antiplatelet use, nonsteroidal anti-inflammatory use, liver disease, and bleeding history, with each additional point scored associated with a 48.7% (95% CI, 38.9%-59.3%; P<0.001) increase in major bleeding in RE-LY. The score had superior performance to the HAS-BLED score in RE-LY (C statistic, 0.73 versus 0.60; P for difference <0.001) and among 12 296 individuals in GARFIELD-AF (C statistic, 0.71 versus 0.66; P for difference = 0.025). The DOAC Score had stronger predictive performance than the HAS-BLED score in both validation cohorts, including 25 586 individuals in COMBINE-AF (C statistic, 0.67 versus 0.63; P for difference <0.001) and 11 945 individuals in RAMQ (C statistic, 0.65 versus 0.58; P for difference <0.001). In individuals with atrial fibrillation potentially eligible for DOAC therapy, the DOAC Score can help stratify patients on the basis of expected bleeding risk.

Cost-effectiveness of apixaban and rivaroxaban in thromboprophylaxis of cancer patients treated with chemotherapy in Spain

BackgroundApixaban and rivaroxaban are two direct-acting oral anticoagulants (DOACs) recommended for thromboprophylaxis in cancer patients treated with chemotherapy in an ambulatory setting. We aimed to assess the cost-utility of thromboprophylaxis with apixaban and rivaroxaban vs no thromboprophylaxis in ambulatory cancer patients starting chemotherapy with an intermediate-to-high risk of venous thromboembolism (VTE), Khorana score ≥ 2 points.MethodsA cost-effectiveness analysis was performed from the perspective of Spain’s National Health System (NHS) using an analytical decision model in the short-term (180 days) and a Markov model in the long-term (5 years). Transition probabilities were obtained from randomized, double-blind, placebo-controlled clinical trials of apixaban and rivaroxaban in adult ambulatory patients with cancer at risk for VTE, treated with chemotherapy (AVERT and CASSINI trials). The costs (€2,021) were taken from Spanish sources. The utilities of the model were obtained through the EQ-5D questionnaire. Deterministic (base case) and probabilistic (second-order Monte Carlo simulation) analyses were conducted.ResultsIn the probabilistic sensitivity analysis, apixaban generated a cost per patient of €1,082 ± 187, with a 95% confidence interval (CI) of €713–1,442, while no prophylaxis produced a cost per patient of €1,146 ± 218, with a 95% CI of €700–1,491, with a saving of €64 per patient and a gain of 0.008 QALYs. Likewise, rivaroxaban provided a cost per patient of €993 ± 133, with a 95% CI of €748–1,310, while no prophylaxis produced a cost per patient of €872 ± 152, with a 95% CI of €602–1,250, with an additional expense of €121 per patient and a gain of 0.008 QALYs.ConclusionsIn thromboprophylaxis of cancer patients, the use of apixaban and rivaroxaban generated similar costs compared to non-prophylaxis, without the difference found being statistically significant, with a clinically insignificant QALY gain.

Abstract P2137: Comparative Effectiveness And Safety Of Rivaroxaban Versus Warfarin In Valvular Atrial Fibrillation: A Systematic Review And Meta-Analysis

Introduction: Patients with valvular atrial fibrillation (AF), which refers to moderate to severe mitral stenosis or mechanical prosthetic heart valves, have an increased risk of ischemic stroke and systemic embolism, which mandates the need for long-term anticoagulation. Still, there are no clear consensus guidelines on the indications of anticoagulation therapy in valvular AF. We aimed to compare the effectiveness of rivaroxaban, a common direct-acting oral anticoagulant (DOAC), to warfarin for preventing thromboembolism in valvular AF patients. Methods: We performed a systematic search of the following databases; PubMed, Cochrane Library, Google Scholar, and EMBASE from inception until February 06, 2023. Results: After screening 389 studies, 8 studies with 68,847 patients have been included in the final analysis. Our meta-analysis did not reveal a significant difference in the occurrence of all-cause mortality between patients who received rivaroxaban and those who received warfarin [RR, 0.97 (95% CI: 0.53-1.76]), p =0.91]. On analysis of the individual studies, rivaroxaban was non-inferior to warfarin with a lower risk of bleeding events [RR, 0. 80 (95% CI: 0.62-1.04), p =0.72], myocardial infarction [RR, 0.56 (95% CI: 0.13-2.47), p =0.44], and stroke/systemic embolism [RR, 0.54 (95% CI: 0. 11-2.55), p = 0.43]. But there was no statistically significant difference between the two groups. Conclusions: With a decreased risk for major adverse events, rivaroxaban appears to have a favorable safety profile, making them a promising alternative to warfarin in treating patients with valvular AF. However, more randomized clinical trials are imperative.

Adverse Clinical Outcomes and Associated Predictors in Rivaroxaban-Treated Atrial Fibrillation Patients With Renal Impairment

Renal impairment confers worse prognosis in patients with atrial fibrillation (AF) but there is scarce evidence about the influence of direct-acting oral anticoagulants in routine clinical practice. Herein, we compared clinical outcomes between patients with AF with and without renal impairment on rivaroxaban and investigated predictors for clinical outcomes in patients with AF with renal impairment. This was a multicenter study including patients with AF on rivaroxaban for at least 6months. During 2.5years follow-up, ischemic strokes (IS)/transient ischemic attacks (TIA)/systemic embolisms (SE)/myocardial infarctions (MI), major bleeding, and major adverse cardiovascular events (MACE) were recorded. Creatinine clearance (CrCl) was estimated using the Cockroft-Gault equation, renal impairment was defined as a CrCl <60ml/min, and 1,433 patients (34.8% with CrCl <60ml/min) were included. Patients with CrCl <60ml/min showed higher event rates for major bleeding (1.87%/year vs 0.62%/year; p=0.003) and MACE (1.97%/year vs 0.62%/year; p=0.002) but similar event rates for IS/TIA/SE/MI (0.66%/year vs 0.67%/year; p=0.955). In patients with renal impairment, CHA2DS2-VASc was associated with higher risk of IS/TIA/SE/MI; HAS-BLED and any dependency level were associated with higher risk of major bleeding; and male gender and heart failure were associated with higher risk of MACE. Antiplatelets were independently associated with increased risk of IS/TIA/SE/MI and MACE. In conclusion, in patients with AF on rivaroxaban, the incidence of IS/TIA/SE/MI did not increase in those with renal impairment, suggesting that rivaroxaban may be an effective option in this subgroup. In patients with AF, male gender, heart failure, dependency, antiplatelets, CHA2DS2-VASc, and HAS-BLED were associated with increased risk of adverse outcomes.

Peri-Procedural Management of Direct-Acting Oral Anticoagulants (DOACs) in Transcatheter Miniaturized Leadless Pacemaker Implantation.

Data on peri-operative management of direct-acting oral anticoagulants (DOACs) during transcatheter pacing leadless system (TPS) implantations remain limited. This study aimed to evaluate a standardized DOAC management regime consisting of interruption of a single dose prior to implantation and reinitiation within 6-24 h; also, patient clinical characteristics associated with this approach were identified. Consecutive patients undergoing standard TPS implantation procedures from two Swiss tertiary centers were included. DOAC peri-operative management included the standardized approach (Group 1A) or other approaches (Group 1B). Three hundred and ninety-two pts (mean age 81.4 ± 7.3 years, 66.3% male, left ventricular ejection fraction 55.5 ± 9.6%) underwent TPS implantation. Two hundred and eighty-two pts (71.9%) were under anticoagulation therapy; 192 pts were treated with DOAC; 90 pts were under vitamin-K antagonist. Patients treated with DOAC less often had structural heart disease, diabetes mellitus, and advanced renal failure. The rate of major peri-procedural complications did not differ between groups 1A (n = 115) and 1B (n = 77) (2.6% and 3.8%, p = 0.685). Compared to 1B, 1A patients were implanted with TPS for slow ventricular rate atrial fibrillation (AF) (p = 0.002), in a better overall clinical status, and implanted electively (<0.001). Standardized peri-procedural DOAC management was more often implemented for elective TPS procedures and did not seem to increase bleeding or thromboembolic adverse events.

Incidence of venous thromboembolism in patients with advanced stage ovarian cancer undergoing neoadjuvant chemotherapy: Is it time for thromboprophylaxis?

ObjectivesOur objectives were to determine the incidence, timing, and risk factors for venous thromboembolisms (VTEs) in patients with advanced stage epithelial ovarian cancer (EOC) who received neoadjuvant chemotherapy (NACT). We explored the utilization of direct-acting oral anticoagulants (DOACs) for VTE treatment. MethodsThis retrospective cohort study included patients with advanced stage EOC receiving NACT followed by interval cytoreductive surgery (ICS) at a single institution. Risk factors were compared between patients with versus without VTE between EOC diagnosis and 180 days after ICS. Bleeding complications were compared between patient who received a DOAC versus non-DOAC. ResultsVTE cases occurred amongst 33 of the 154 (21.4%) patients with 4 (2.6%) concurrent with EOC diagnosis, 9 (5.8%) between EOC diagnosis and NACT start, 13 (8.4%) between NACT start and ICS, and 7 (4.5%) within 180 days after ICS. There were no statistically significant differences in risk factors assessed (age, body mass index, functional status, histology, Khorana score, and smoking history) between patients with versus without VTE. Eleven patients (33.3%) received a DOAC for VTE treatment. There were no significant differences in number of intraoperative blood transfusions (p = 0.38), blood loss (p = 0.95), or bleeding complications (p = 0.53) between patients treated with a DOAC versus a non-DOAC. ConclusionThere is a high incidence of VTE events (21.4%) in patients with advanced stage EOC undergoing NACT. Two-thirds of the VTEs may have been prevented with thromboprophylaxis as they occurred between EOC diagnosis and ICS. These data support consideration of thromboprophylaxis in all patients with advanced stage EOC undergoing NACT.

Determination of the Potential Clinical Benefits of Small Molecule Factor XIa Inhibitors in Arterial Thrombosis.

Anticoagulants are the mainstay for the prevention and treatment of thrombosis. However, bleeding complications remain a primary concern. Recent advances in understanding the contribution of activated factor XI (FXIa) in arterial thrombosis with a limited impact on hemostasis have led to the development of several FXIa-targeting modalities. Injectable agents including monoclonal antibodies and antisense oligonucleotides against FXIa have been primarily studied in venous thrombosis. The orally active small molecules that specifically inhibit the active site of FXIa are currently being investigated for their antithrombotic activity in both arteries and veins. This review focuses on a discussion of the potential clinical benefits of small molecule FXIa inhibitors, mainly asundexian and milvexian, in arterial thrombosis based on their pharmacological profiles and the compelling results of phase 2 clinical studies. The preclinical and epidemiological basis for the impact of FXIa in hemostasis and arterial thrombosis is also addressed. In recent clinical study results, asundexian appears to reduce ischemic events in patients with myocardial infarction and minor-to-moderate stroke, whereas milvexian possibly provides benefits in patients with minor stroke or high-risk transient ischemic attack (TIA). In addition, asundexian and milvexian had a minor impact on hemostasis even in combination with dual-antiplatelet therapy. Other orally active FXIa inhibitors also produce antithrombotic activity in vivo with low bleeding risk. Therefore, FXIa inhibitors might represent a new class of direct-acting oral anticoagulants (DOACs) for the treatment of thrombosis, although the explicit clinical positions of asundexian and milvexian in patients with ischemic stroke, high-risk TIA, and coronary artery disease require confirmation from the outcomes of ongoing phase 3 trials.