Direct Oral Anticoagulants Prescription Research Articles

Abstract 15396: Atrial Fibrillation Bleeding Risk and Prediction While Treated With Direct Oral Anticoagulants in Warfarin Naïve and Experienced Patients

Introduction: Direct oral anticoagulants (DOAC) are guideline-recommended over warfarin for stroke prevention in atrial fibrillation (AF). However, patients who are DOAC eligible are commonly maintained on warfarin. We sought to evaluate bleeding risk and prediction while on DOAC treatment (both for warfarin-naïve and -experienced patients) as compared to warfarin. Methods: We performed a retrospective cohort study using data from the Veteran Affairs health care system. We included patients with a prescription for warfarin and/or DOAC from 10/1/2010 to 9/30/2017 with an AF encounter in the 90 days prior to 30 days after prescription. We categorized DOAC treated patients as warfarin-naïve or -experienced and performed an on-treatment analysis to determine bleeding incidence and HAS-BLED score discrimination. In adjusted analyses, we compared risk of bleeding while treated with DOAC (both for warfarin-naïve and -experienced patients) to warfarin. Results: The analysis cohort included 99,143 patients treated with warfarin (71±10 years, HAS-BLED 2.6±1.2) and 73,732 and 26,760 patients treated with DOAC who were warfarin-naïve (74±10 years, HAS-BLED 2.4±1.0) and -experienced (71±9 years, HAS-BLED 2.8±1.1), respectively. DOAC patients with warfarin experience had more prior bleeds (DOAC, warfarin-experienced: 11.9%; DOAC, warfarin-naïve: 4.5%; warfarin: 6.2%; p<0.001 for both). Risk of intracranial bleeding was substantially lower while on DOAC treatment (both for warfarin-naïve and -experienced patients) as compared to warfarin ( Table ). HAS-BLED discrimination for bleeding outcomes, intracranial or any bleeding, was modest ( Table ). Conclusion: DOAC treatment had a favorable safety profile compared to warfarin treatment, even for DOAC treated patients with warfarin-experience who had more prior bleeds. These data argue against maintaining DOAC eligible patients on warfarin therapy regardless of HAS-BLED score.

Switching across direct oral anticoagulants: a real-life-setting pilot prospective study.

Crossover between direct oral anticoagulants (DOACs) has been underinvestigated, but happens frequently in clinical practice. The purpose of this study was to evaluate causes, rates and outcomes of a DOAC-to-DOAC switch. Patients receiving their first DOAC prescription at the Anticoagulation Center, Cardiology Dept, Bologna-Bellaria Hospital in 2017-2018 were consecutively included and prospectively followed up. DOAC-to-DOAC switch was the main outcome; causes of switch (cardiovascular events and noncardiovascular drug-related adverse events) had direct biannual assessment before and after the switch. Among 300 patients enrolled (mean age = 79.3 years, mean follow-up = 1.5 years), with no difference in cardiovascular risk factors depending on index DOAC, 13% underwent DOAC-to-DOAC switch, minor bleeding and noncardiovascular adverse events being the most frequent causes. Dabigatran carried a three-fold increase in risk of switch compared with other DOACs, but the mean age of patients who switched was 83. Factors leading to switch resolved in 87% of cases afterwards. Annual rates of cardiovascular/noncardiovascular V events did not differ before and after the switch. DOAC-to-DOAC switch happens in 9% of patients using DOAC each year, and seems not to impact rates of cardiovascular events after switch. Dabigatran, in the elderly, might be associated with a higher risk of DOAC-to-DOAC switch. Further studies are needed to confirm the long-term safety and effectiveness of switching paradigm.

Association of Medicaid Expansion With Rates of Utilization of Cardiovascular Therapies Among Medicaid Beneficiaries Between 2011 and 2018.

The Affordable Care Act expanded Medicaid eligibility allowing low-income individuals greater access to health care. However, the uptake of state Medicaid expansion has been variable. It remains unclear how the Medicaid expansion was associated with the temporal trends in use of evidence-based cardiovascular drugs. We used the publicly available Medicaid Drug Utilization and Current Population Survey to extract filled prescription rates per 1000 Medicaid beneficiaries of statins, antihypertensives, P2Y12 inhibitors, and direct oral anticoagulants. We defined expander states as those who expanded Medicaid on or before January 1, 2014, and nonexpander states as those who had not expanded by December 31, 2018. Difference-in-differences (DID) analyses were performed to compare the association of the Medicaid expansion with per-capita cardiovascular drug prescription rates in expander versus nonexpander states. Between 2011 and 2018, the total number of prescriptions among all Medicaid beneficiaries increased, with gains of 89.7% in statins (11.0 to 20.8 million), 76% in antihypertensives (35.3 to 62.2 million), and 37% in P2Y12 inhibitors (1.7 to 2.3 million). Medicaid expansion was associated with significantly greater increases in quarterly prescriptions (per 1000 Medicaid beneficiaries) of statins (DID estimate [95% CI]: 22.5 [16.5-28.6], P<0.001), antihypertensives (DID estimate [95% CI]: 63.2 [47.3-79.1], P<0.001), and P2Y12 inhibitors (DID estimate [95% CI]: 1.7 [1.2-2.2], P<0.001). Between 2013 and 2018, >75% of the expander states had increases in prescription rates of both statins and antihypertensives. In contrast, 44% of nonexpander states saw declines in statins and antihypertensives. The Medicaid expansion was not associated with higher direct oral anticoagulants prescription rates (DID estimate [95% CI] 0.9 [-0.3 to 2.1], P=0.142). The 2014 Medicaid expansion was associated with a significant increase in per-capita utilization of cardiovascular prescription drugs among Medicaid beneficiaries. These gains in utilization may contribute to long-term cardiovascular benefits to lower-income and previously underinsured populations.

Prescribing Pattern of Oral Anticoagulants in Patients With Obesity

Introduction: There is limited efficacy and safety data for direct oral anticoagulants (DOACs) in patients with obesity, and it has been suggested to avoid DOACs in this patient population. Objective: Describe the prescribing pattern of oral anticoagulants in obese patients in an urban university setting and assess efficacy, safety, and adherence. Methods: Retrospective, cohort study in patients ≥18 years with a history of VTE and/or atrial fibrillation. Patients with a BMI >40 kg/m2 and/or weight >120 kilograms and a prescription for warfarin or a DOAC from August 25, 2014 until August 25, 2017 are included. The primary outcome is the number of warfarin or DOAC prescriptions. Secondary outcomes include thromboembolism and bleeding events. Patient adherence was evaluated using time in therapeutic range (TTR), adherence rate to clinic appointments, and medication possession ratio (MPR). Results: Of the 276 patients who met eligibility criteria, 158 (57.2%) were prescribed warfarin and 118 (42.8%) were prescribed a DOAC. There was no difference in the rate of stroke or recurrent VTE between groups (3.2% vs. 3.4%, p = 0.944). There was also no difference in the rate of bleeding between groups (16.1% vs. 17.8%, p = 0.707). The TTR for the warfarin group was 44.8 ± 23%, and appointment adherence was 78.6 ± 20%. The MPR for the DOAC group was 0.93 ± 0.24. Conclusions: Despite limited data in obese patients, DOACs are prescribed in this population. Results suggest no difference in safety and efficacy compared to warfarin, but barriers to quality anticoagulation may exist in this population.

Elderly people are inherently sensitive to the pharmacological activity of rivaroxaban: implications for DOAC prescribing

According to both trial and clinical data on direct oral anticoagulants (DOACs) elderly patients are at greatest risk of bleeding. It is unclear whether age intrinsically affects anticoagulation response. To investigate the age-related sensitivity to DOACs, we compared the pharmacological activity of the direct factor Xa inhibitor, rivaroxaban, between young and elderly subjects ex-vivo. 36 fit elderly and 30 fit young subjects [median (IQR) age: 83(75–87) vs 30(26–38) years] provided a blood sample. Clotting parameters were measured in the resultant plasma samples incubated with rivaroxaban (100–500 ng/ml). Parametric, non-parametric tests and regression lines adjusted for rivaroxaban concentration and baseline values were used to compare data. Rivaroxaban produced a greater prolongation of both Prothrombin Time (PT) and modified Prothrombin Time (mPT) (both p < 0.001) in the elderly compared to young subjects (with difference in mean PT increasing from 1.6 to 6.1s and for mPT from 23.5 to 71.1s at 100 ng/ml and 500 ng/ml plasma rivaroxaban concentration, respectively). Factor X and factor II activity was significantly lower in the elderly in the presence of rivaroxaban (p < 0.001 for both). Rivaroxaban prolonged time-based parameters and suppressed the amount of thrombin generation to a significantly greater extent in the elderly compared to young subjects [%change from baseline for Endogenous Thrombin Potential (ETP): − 35.0 ± 4.4 vs − 29.8 ± 7.4 nM*min; p = 0.002]. The use of validated DOAC assays will be of considerable benefit for monitoring elderly patients who, because of their increased sensitivity to rivaroxaban, may require lower doses of the drug for therapeutic anticoagulation.

Clinical and budget impacts of changes in oral anticoagulation prescribing for atrial fibrillation

ObjectiveTo assess temporal clinical and budget impacts of changes in atrial fibrillation (AF)-related prescribing in England.MethodsData on AF prevalence, AF-related stroke incidence and prescribing for all National Health Service general...

Early prescription of direct oral anticoagulant for the treatment of intermediate-high risk pulmonary embolism: a multi-center, observational cohort study

ObjectivesThe safety and efficacy of direct oral anticoagulants (DOACs) in intermediate-high risk pulmonary embolism (PE) are unknown. The aims of the present study were to describe outcomes of patients receiving early apixaban or rivaroxaban prescription rather than the recommended delayed prescription strategy. MethodsRetrospective post-hoc analysis based on prospectively collected data from a multicenter cohort including all consecutive PE patients stratified as intermediate-high risk. Group definitions were: early group with DOAC prescription <72 h after admission; delayed group with DOAC prescription between 72 h and discharge. The 30-day primary efficacy outcome was a clinical composite of all-cause death and hemodynamic decompensation. The 30-day primary safety outcome was major bleeding. ResultsAmong 2411 patients admitted with PE, 302 were treated with a DOAC for an intermediate-high risk PE: 34.2% in the early group and 65.9% in the delayed group. The primary outcome occurred in 4.8% (including 1 death and 4 hemodynamic decompensations) in the early DOAC group and in 9.0% in the delayed DOAC group (OR, 0.44, 95% CI 0.15–1.30). The rate of major bleeding did not differ between groups (OR, 0.99; 95% CI 0.45–2.18). The length of stay was numerically shorter in the early group whereas the other outcomes did not differ significantly. ConclusionThe rate of 30-day outcomes was low in patients receiving a DOAC earlier after admission. Patients in the early DOAC group had a numerically shorter length of stay, with similarly low rates of death and bleeding, and similar RV function recovery compared to the delayed strategy.

The Number of Concomitant Drugs and the Safety of Direct Oral Anticoagulants in Routine Care Patients with Atrial Fibrillation.

Background The benefit of direct oral anticoagulants (DOACs) versus vitamin K antagonists (VKAs) on major bleeding was less prominent among atrial fibrillation (AF) patients with polypharmacy in post-hoc randomized controlled trials analyses. Whether this phenomenon also exists in routine care is unknown. The aim of the study is to investigate whether the number of concomitant drugs prescribed modifies safety and effectiveness of DOACs compared with VKAs in AF patients treated in general practice. Study Design Adult, nonvalvular AF patients with a first DOAC or VKA prescription between January 2010 and July 2018 were included, using data from the United Kingdom Clinical Practice Research Datalink. Primary outcome was major bleeding, secondary outcomes included types of major bleeding, nonmajor bleeding, ischemic stroke, and all-cause mortality. Effect modification was assessed using Cox proportional hazard regression, stratified for the number of concomitant drugs into three strata (0–5, 6–8, ≥9 drugs), and by including the continuous variable in an interaction term with the exposure (DOAC vs. VKA). Results A total of 63,600 patients with 146,059 person-years of follow-up were analyzed (39,840 person-years of DOAC follow-up). The median age was 76 years in both groups, the median number of concomitant drugs prescribed was 7. Overall, the hazard of major bleeding was similar between VKA-users and DOAC-users (hazard ratio [HR] 0.98; 95% confidence interval [CI] 0.87–1.11), though for apixaban a reduction in major bleeding was observed (HR 0.81; 95% CI 0.68–0.98). Risk of stroke was comparable, while risk of nonmajor bleeding was lower in DOAC users compared with VKA users (HR 0.92; 95% CI 0.88–0.97). We did not observe any evidence for an impact of polypharmacy on the relative risk of major bleeding between VKA and DOAC across our predefined three strata of concomitant drug use ( p -value for interaction = 0.65). For mortality, however, risk of mortality was highest among DOAC users, increasing with polypharmacy and independent of the type of DOAC prescribed ( p -value for interaction <0.01). Conclusion In this large observational, population-wide study of AF patients, risk of bleeding, and ischemic stroke were comparable between DOACs and VKAs, irrespective of the number of concomitant drugs prescribed. In AF patients with increasing polypharmacy, our data appeared to suggest an unexplained yet increased risk of mortality in DOAC-treated patients, compared with VKA recipients.

Dabigatran, the oral anticoagulant of choice at discharge in patients with non-valvular atrial fibrillation and COVID-19 infection: the ANIBAL protocol.

Atrial fibrillation is a frequent complication among patients with severe coronavirus disease-2019 (COVID-19) infection. Both direct and indirect mechanisms through COVID-19 have been described to explain this relationship. COVID-19 infection increases the risk of developing both arterial and venous thrombotic complications through systemic coagulation activation, leading to increased mortality. Chronic oral anticoagulation is essential to reduce the thromboembolic risk among AF patients. Switching to low-molecular-weight heparin has been recommended during hospitalization for COVID-19 infection. Of note, at discharge, the prescription of direct oral anticoagulants may offer some advantages over vitamin K antagonists. However, oral anticoagulants should only be prescribed after the consideration of drug–drug interactions with antiviral therapies as well as of the risk of hepatotoxicity, which is common among individuals with severe COVID-19 pneumonia. Not all anticoagulants have the same risk of hepatotoxicity; dabigatran has shown a good efficacy and safety profile and could have a lower risk of hepatotoxicity. Furthermore, its metabolism by cytochrome P450 is absent and it has a specific reversal agent. Therefore, dabigatran may be considered as a first-line choice for oral anticoagulation at discharge after COVID-19 infection. In this review, the available information on the antithrombotic management of AF patients at discharge after COVID-19 infection is updated. In addition, a practical algorithm, considering renal and liver function, which facilitates the anticoagulation choice at discharge is presented.

Prescriber compliance to direct oral anticoagulant labels and impact on outcomes in Thailand.

This study aimed to evaluate the prescriber compliance to the approved labels of direct oral anticoagulants (DOACs) and impact of appropriateness of dosing on clinical outcomes. A retrospective study was conducted using simple-stratified random sampling of adult patients receiving ≥6 months of DOACs for various indications during 2013-2017 in 10 tertiary care hospitals. Patients were classified into 3 dosing groups including approved dose, underdosing and overdosing based on the Thai Food and Drug Administration-approved labels. Cox proportional hazard models were used to evaluate the impact of different dosings on thromboembolic and bleeding events. From 1200 patients included in the data analysis, prescribing of DOACs was consistent with the approved indications in 1130 cases (94.2%) while 70 patients (5.8%) received DOACs despite having contraindications or with off-label usage. Among 1026 cases of dosing evaluation cohort, 688 patients (67.1%) received approved doses. There were 227 (21.9%) and 110 (10.7%) cases of underdosing and overdosing, respectively. Multivariate analysis showed that underdosing was associated with an increased risk of thromboembolism 3.023 (95% confidence interval [CI]: 1.291-7.080; P = .011) while overdosing was associated with an increased risk of bleeding requiring hospitalization (adjusted hazard ratio, 3.045; 95% CI, 1.501-6.178; P = .002) and Bleeding Academic Research Consortium type 2 or more (adjusted hazard ratio, 2.196; 95% CI, 1.083-4.452; P = .029). Prescribers' compliance to approved indications were high. However, 1/3 of DOAC prescriptions were inconsistent with approved dosing. Dosing deviation was associated with an increase in adverse clinical outcomes.

Effectiveness and Safety of Direct Oral Anticoagulants in the Secondary Stroke Prevention of Elderly Patients: Ljubljana Registry of Secondary Stroke Prevention

The results of randomised clinical trials (RCTs) on direct oral anticoagulants (DOACs) for stroke prevention in patients with nonvalvular atrial fibrillation (NVAF) can mostly be applied to primary prevention in relatively young patients, since only a minority of patients included in these trials were receiving DOACs for secondary prevention. The real-life secondary prevention subgroup, comprising mostly elderly and high-risk patients, remains a point of interest where further exploration is needed. Our objective was to explore the effectiveness and safety of DOACs for secondary prevention in the real-life conditions. In a six-year (2012-2018) period all consecutive patients with a history of transient ischaemic attack (TIA) or stroke, recorded NVAF and prescription of DOAC, were included in this single-centre registry. Choice of the DOAC and dose was based on the discretion of the attending clinician. Data regarding recurrent stroke/TIA or other embolic events, intracranial haemorrhage, other major bleeding, adherence and potential changes of therapy were collected and analysed. During the study period, 566 patients were prescribed a DOAC for secondary stroke prevention, and follow-up data were available for 510 patients, with an average observational time of 2.6years. The mean age of patients was 77.9 ± 8.7years. The mean CHA2DS2-VASc and HAS-BLED scores were 5.1 ± 1.2 and 2.4 ± 0.6, respectively. Dabigatran was prescribed in 66%, apixaban in 21% and rivaroxaban in 13% of patients; 58% of patients were prescribed the reduced dose of DOAC. The overall yearly incidence of recurrent stroke, major bleeding and intracranial bleeding was 1.7%, 1.6% and 0.2%, respectively. Thus, we found similar effectiveness and safety of both standard and reduced dose of DOACs for secondary stroke prevention, compared to the RCT and large registries. Our real-life data study suggests that secondary stroke prevention with DOACs is as effective and safe as primary prevention, both in standard and reduced doses, in a typical group of patients who are older than patients included in RCTs.

HCF-ANMCO/AICPR/GIEC/ITAHFA/SICOA/SICP/SIMG/SIT Cardiological Societies Council Consensus document: Anticoagulant therapy in venous thromboembolism and atrial fibrillation of the patient with cancer. Current knowledge and new evidence

Venous thromboembolism (VTE), including pulmonary embolism and deep venous thrombosis, either symptomatic or incidental, is a common complication in the history of cancer disease. The risk of VTE is 4-7-fold higher in oncology patients, and it represents the second leading cause of death, after cancer itself. In cancer patients, compared with the general population, VTE therapy is associated with higher rates of recurrent thrombosis and/or major bleeding. The need for treatment of VTE in patients with cancer is a challenge for the clinician because of the multiplicity of types of cancer, the disease stage and the imbricated cancer treatment. Historically, in cancer patients, low molecular weight heparins have been preferred for treatment of VTE. More recently, in large randomized clinical trials, direct oral anticoagulants (DOACs) demonstrated to reduce the risk of VTE. However, in the "real life", uncertainties remain on the use of DOACs, especially for the bleeding risk in patients with gastrointestinal cancers and the potential drug-to-drug interactions with specific anticancer therapies.In cancer patients, atrial fibrillation can arise as a perioperative complication or for the side effect of some chemotherapy agents, as well as a consequence of some associated risk factors, including cancer itself. The current clinical scores for predicting thrombotic events (CHA2DS2-VASc) or for predicting bleeding (HAS-BLED), used to guide antithrombotic therapy in the general population, have not yet been validated in cancer patients. Encouraging data for DOAC prescription in patients with atrial fibrillation and cancer are emerging: recent post-hoc analysis showed safety and efficacy of DOACs for the prevention of embolic events compared to warfarin in cancer patients. Currently, anticoagulant therapy of cancer patients should be individualized with multidisciplinary follow-up and frequent reassessment. This consensus document represents an advanced state of the art on the subject and provides useful notes on clinical practice.

Prescription of oral anticoagulants and antiplatelets for stroke prophylaxis in atrial fibrillation: nationwide time series ecological analysis.

To investigate trends in the prescription of oral anticoagulants (OACs) and antiplatelet agents for atrial fibrillation (AF). Prescription data for 450518 patients with AF from 3352 General Practices in England, was obtained from the GRASP-AF registry, 2009-2018. Annualized temporal trends for OAC and antiplatelet prescription were reported according to eligibility based on stroke risk (CHADS2 or CHA2DS2-VASc scores ≥1 or >2, respectively). From 2009 to 2018, the prevalence of AF increased from 1.6% [95% confidence interval (CI) 1.5-1.7%] to 2.4% (2.3-2.5%), and for those with AF the proportion prescribed OAC increased from 47.6% to 75.0% (P-trend < 0.001; relative risk 1.57, 95% CI 1.55-1.60) and for antiplatelet decreased from 37.4% to 9.2% (P-trend < 0.001). In early-years (2009-2013), eligible patients aged ≥80 years were less likely to be prescribed OAC than patients aged <80 years [odds ratio (OR) 0.55, 95% CI 0.51-0.59 for CHADS2≥1 in 2009] (all P-trends < 0.001). This 'OAC prescription gap' reduced over the study period (OR 0.93, 0.90-0.96 in 2018). Whilst the prescription of direct oral anticoagulant (DOAC) as a proportion of all OAC increased from 0.1% (95% CI 0.0-0.2%) in 2011 to 58.8% (58.4-59.2%) in 2018, it was inversely associated with patient age (P-trend < 0.001) and their risk of stroke. Between 2009 and 2018, in England, the use of OAC for stroke prophylaxis in AF increased, with DOAC accounting for over half of OAC uptake in 2018. Despite a reduction in the OAC-prescription gap, a new paradox exists relating to DOAC prescription for the elderly and those at higher risk of stroke.

Risk of fracture in patients with non-valvular atrial fibrillation initiating direct oral anticoagulants vs. vitamin K antagonists.

To determine the risk of fracture associated with direct oral anticoagulants (DOACs) compared with vitamin K antagonists (VKAs) in patients with non-valvular atrial fibrillation (NVAF), accounting for cumulative duration of use. Using Quebec administrative healthcare databases, we formed a cohort of all patients aged 40 years or older newly diagnosed with NVAF, who filled a first prescription for DOACs or VKAs between 2011 and 2014. Exposure was modelled as a time-varying variable whereby patients were considered unexposed up to 180 days of cumulative duration of use (to account for a biologically meaningful exposure) and exposed thereafter. The final cohort included 10306 new users of DOACs and 15357 new users of VKAs. After propensity score-based fine stratification and weighting, use of DOACs for 180 days or greater was associated with a 35% decreased risk of fracture [crude incidence rates 7.5 vs. 15.3 per 1000 person-years; adjusted hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.46-0.91] compared to VKA duration ≥180 days. Direct oral anticoagulants use was also associated with a lower risk of hip fracture (HR 0.51, 95% CI 0.31-0.86) compared with VKAs. There was no difference in the rate of fracture for shorter duration of use (HR 1.10; 95% CI 0.79-1.53). The risk was not modified by age, sex, chronic kidney disease, osteoporosis, history of fracture or falls. Prolonged use of DOACs is associated with a lower risk of fracture compared with VKAs. These findings support the first-line recommendation for DOACs in patients with NVAF.

Évaluation des prescriptions d’anticoagulants oraux directs (AOD) en gériatrie hospitalière sur 3 ans

Direct oral anticoagulants (DOACs) are an attractive choice for patients in need of anticoagulant therapy, but available data on their specific use in real life conditions in elderly patients are limited. The purpose of this study is to describe the characteristics and evolution of the prescriptions in geriatric hospital. The prescriptions of patients treated with DOACs in two university geriatric hospitals were analyzed retrospectively over 3 years. Co-treatment and hemorrhagic and thrombotic complications were studied. A total of 399 patients were included, including 10 in 2015, 110 in 2016 and 279 in 2017. The average age was 85 years old, 40% of patients had a weight of less than 60kg, and more than 50% had an estimated creatinine clearance of less than 50mL/min. The most common indication was atrial fibrillation in 85%. In 32% of cases, the dosage of DOACs was not adapted to official recommendations. Underdosages accounted for approximately 60% of dosage errors. Twelve patients (3% of the cohort) had a thrombotic event under DOACs, associated with an underdosing in 50% of them. 41 patients, or 10% of the cohort, had a hemorrhagic event under DOACs, with 12 patients (29%) having a pharmacologic risk factor (10 overdoses and 2 drug interactions). The prescription of DOACs in elderly patients has increased considerably in recent years. However, dosing errors remain frequent (overdoses as underdoses), associated with hemorrhagic or thrombotic events. Similarly, drug interactions should be known as they are a risk factor for avoidable under- or overdose. Improving prescriptions of DOACs in geriatrics needs to respect the rules of good practice, to regularly reassess renal function, and to transmit observations of adverse effects to pharmacovigilance centers.

Direct oral anticoagulants for patients aged over 80 years in nonvalvular atrial fibrillation: the impact of frailty.

In patients aged at least 80 years, atrial fibrillation is responsible for significant morbidity and mortality, with a high incidence of stroke. Four new direct oral anticoagulants (DOACs) have been introduced in Italy for the prevention of thromboembolism. Their safety and efficacy in the elderly have already been confirmed. Frailty is frequently associated with aging, but only a few studies have paid attention to interactions between frailty and anticoagulation therapy. We retrospectively evaluated the effectiveness and safety of DOACs in a population aged at least 80 years. Frailty was appraised using an adaptation of the Reported Edmonton Frail Scale, considering a value at least 8 (on a scale from 0 to 18). The majority (644/731) of patients remained on DOACs for more than 1 year. A total of 19 patients experienced a thrombotic event while on anticoagulation (1.11 events per 100 person-years) and 26 patients a major bleeding episode (1.52 events per 100 person-years). The probability of interrupting therapy increased significantly with frailty [hazard ratio 2.91 with confidence interval (CI) 2.15-3.92 at univariate analysis, hazard ratio 2.80 with CI 2.03-3.86 at multivariate]; frailty showed a significant impact also on major bleeding (hazard ratio 3.28 with CI 1.45-7.37 at univariate analysis, hazard ratio 3.56 with CI 1.58-8.01 at multivariate). Our study highlights how DOACs are a safe and effective option for anticoagulation, even in frail elderly people; the introduction of these drugs is leading to an increased use of anticoagulation therapy in this population. Prospective trials will be needed to reinforce these results and to consider new variables in the thrombotic and hemorrhagic risk scores underlying the prescription of DOACs.

76Causes, safety and outcomes of switching from the Initial direct oral anticoagulant to another in patients with non-valvular atrial fibrillation from a single-center prospective study

Abstract Background Crossover between direct oral anticoagulants (DOACs) in real-life setting has been under investigated, with electronic registry-based study missing minor bleedings and minor ischemic events. The purpose of this study was to evaluate the switch from a DOAC to another DOAC, the reasons and the clinical events which happened after the switch. Methods Patients (pts) receiving first DOAC prescription at the Anticoagulation Center from February 2018 to September 2019 were consecutively included and followed. Causes of switch/dosage change as well as events or adverse events not leading to switch were registered. Results Overall, 300 pts were included, mean age 79.3 ± 8.5, male 53.7% (n = 161). 220 pts were received DOAC being naïve (70.7%), while 88 (29.3%) transitioned from vitamin K antagonists. Mean follow-up was 1.5 years from first DOAC prescription. Most prescribed DOACs was rivaroxaban (n = 107), followed by apixaban (n = 82), edoxaban (n = 59) and dabigatran (n = 52). No significant differences in age, gender, CHA2DS2VASc or HASBLED score was detected. Throughout follow-up, 61 patients (20.3%) needed changes in anticoagulation regimen. 24 patients changed DOAC dosage (8%), while 40 patients changed anticoagulants (13.3%), 39 switched from DOAC to another DOAC, 1 from DOAC to warfarin. Annual DOAC-to-DOAC switching rate was 15.0% (95%CI 10.8-20.3). Prevalence of switch varied across DOACs: 28.8% of pts taking dabigatran switched vs 11.0%, 10.2% and 9.3% of those taking apixaban, edoxaban and rivaroxaban respectively (p &amp;lt; 0.05). Apixaban was the most commonly preferred DOAC after switch, with 43% of pts receiving it after crossover. Causes of switch included minor bleeding (n = 15), major bleeding (n = 3), non-cardiovascular adverse events (n = 14), drug interaction or surgery (n = 4), renal function worsening (n = 2) and low compliance (n = 1). Comparative risk analysis revealed that prescription of dabigatran was associated with a 3-fold increase in risk of switching treatment (OR 3.59, 95%CI 2.09-6.19) compared to other DOACs. Apixaban, rivaroxaban and edoxaban seemed to have similar profile in terms of long-term adherence to treatment . Cox regression analysis, taking into account age, weight, CHA2DS2VASc and HASBLED scores, revealed significant differences in temporal distribution of crossover, with pts in dabigatran more likely to change treatment (HR 2.5, p &amp;lt; 0.05). After switching, 34 out of 39 pts remained free from cardiovascular events and non-cardiovascular adverse events. One pt had minor bleeding, only 1 had major (non-fatal) bleeding, and none reported compliance issues. Non-cardiovascular adverse events completely resolved after switch . Conclusion Minor bleeding and non cardiovascular adverse events are the most common causes of switch, which has a rate as high as 15% year. Crossover between DOACs seems safe, and might therefore be considered after minor bleeding and non-cardiovascular adverse events

Uptake of direct oral anticoagulants in primary care: an ecological and economic study.

BackgroundClinical trials indicate that direct oral anticoagulants (DOACs) are as effective as warfarin at preventing ischaemic stroke. It is unclear, however, whether relative changes in DOAC uptake have affected clinical and economic outcomes in practice.AimTo investigate variations in DOAC uptake and the relationship with hospital admissions and cost.Design & settingAn ecological study using electronic administrative records from England, April 2012 to March 2017.MethodMultivariable regression was used to model practice variation in DOAC prescribing, and the relationship with clinical and economic outcomes.ResultsIn quarter 1 of 2017, 55.0% of the 2 695 262 patients dispensed an anticoagulant were given a DOAC. There was a two-fold difference in odds of dispensing DOACs between clinical commissioning groups (CCGs) between those with the highest and lowest usage of these drugs. Increases in the relative uptake of DOACs were not associated with hospital admissions for ischaemic stroke (adjusted incidence rate ratio [IRR] = 1.00; 95% confidence intervals [CI] = 0.999 to 1.001), nor gastrointestinal or intracranial bleeds (IRR = 1.001; 95% CI = 1.000 to 1.002). In 2017, quarter 1, CCGs spent £9247 (inter-quartile range £7751 to £10 853) per 1000 patients on anticoagulants. The marginal effect of a 5% increase in DOAC uptake was associated with a £17.95 (£8.75 to £27.15) increase in total costs, per 1000 patient population.ConclusionThere were significant differences in the relative uptake of DOACs across practices, with greater costs but no reduction in hospital admissions in those with higher levels of dispensing. Findings indicate that clinical and economic benefits of DOACs identified by clinical trials are not realised in practice.

Incidence of Direct Oral Anticoagulant Prescriptions in Kidney Transplant Recipients in Ontario, Canada

BackgroundKidney transplant recipients (KTRs) are routinely excluded from direct oral anticoagulant (DOAC) trials. Given the lack of safety and efficacy data in this population, we examined real-world prescribing practices of DOACs in KTRs. MethodsWe conducted a retrospective cohort study using linked administrative data sets in Ontario, Canada. All adult KTRs (n = 5580) from June 23, 2009, to March 31, 2017, were included. The primary outcomes were the first prescription for a DOAC or warfarin. Patients were censored on graft failure, death, or end of follow-up. ResultsThe mean age was 55 (SD, 14) years; 63% were male, and 65% had received a deceased donor kidney. Over a median follow-up of 5.5 and 4.7 years, 224 KTRs (4.0%) and 824 KTRs (14.8%) were prescribed DOACs and warfarin, respectively. The rates of DOAC and warfarin prescriptions were 8.1 and 32.6 per 1000 person-years, respectively. Older age, receipt of a kidney transplant in more recent years, and higher baseline estimated glomerular filtration rate were associated with DOAC prescription compared with warfarin. Patients with multiple comorbidities and a history of deep venous thromboembolism had a lower risk of DOAC prescription compared with warfarin. When examined by era, the incidence rate of both DOAC and warfarin prescriptions increased significantly over time. ConclusionsDespite limited safety and efficacy data, DOACs are prescribed to KTRs. However, warfarin still remains more commonly prescribed in this selected patient population. Anticoagulant prescriptions overall are on the rise in KTRs. Further study is needed to determine the safety and efficacy of DOACs in KTRs.

Algorithm for the Choice of Anticoagulant for Patients with Atrial Fibrillation

Aim. To evaluate the effectiveness of the anticoagulant choice algorithm in the prevention of complications of atrial fibrillation (AF). Material and methods. Patients with AF (n=98) were included into observational prospective study. The level of adherence to treatment, risk of food interactions and presence of CYP2C9 and VKORC1 genes mutations were determined at the initial examination. These indicators were necessary to specify an eligible anticoagulant according to the evaluated algorithm. Therapy was prescribed by the attending physician. Hemorrhagic and thromboembolic complications were assessed at the next examination after 24 weeks. Results. Hemorrhagic complications were observed in 31.6% of patients during the follow-up. Their number was comparable in individuals taking antiplatelet agents and direct oral anticoagulants (DOACs) (χ2=1.44; p&lt;0.49, Pearson) and significantly more in individuals taking warfarin (as compared to DOACs: χ2=25.08; p&lt;0.000, Pearson; and antiplatelet agents: χ2=34.32; p&lt;0.000, Pearson). Thromboembolic complications were reported in 8.16% of patients. Their number was more in patients taking DOACs than warfarin (χ2=7.03; p&lt;0.03, Pearson). Patients who had to take DOACs according to the algorithm, but in the study took warfarin, demonstrated significantly greater number of thromboembolic complications, with a comparable number of hemorrhagic complications. Patients who could take warfarin according to the algorithm, but in the study took DOACs, had significantly greater number of thromboembolic complications, with a comparable number of hemorrhagic complications. Conclusion. The results of the study demonstrated the potential for reduction in complications, especially thromboembolic, in the choice of anticoagulant using the algorithm; and reduction in complications of therapy, primarily with warfarin, due to the initial prescription of DOACs. The proposed approach, which consists in using the quantitative assessment of adherence to treatment, and only if necessary supplemented by the assessment of food preferences and/or pharmacogenetic studies, contributes to the treatment optimization.