Safety Of Non-vitamin K Oral Anticoagulants Research Articles

Outcomes of non-vitamin K oral anticoagulants for secondary prevention in ischemic stroke with atrial fibrillation

Previous studies have rarely investigated the role of non-vitamin K oral anticoagulants (NOAC) and warfarin in the secondary prevention of ischemic stroke patients with nonvalvular atrial fibrillation (NVAF). In this study, we compared the effectiveness and safety of NOAC and warfarin for secondary prevention in Korean ischemic stroke patients with NVAF. Based on the Korean National Health Insurance Service Database, this study included 21,064 oral anticoagulants-naïve acute ischemic stroke patients with NVAF between July 2015 and June 2019. The main study outcomes included ischemic stroke, systemic embolism, major bleeding, and death. During the observational periods, NOAC users had a significantly decreased risk of ischemic stroke + systemic embolism (adjusted hazard ratio [aHR] 0.86; 95% confidence interval [CI] 0.78–0.95), ischemic stroke (aHR 0.89; 95% CI 0.81–0.99), major bleeding (aHR 0.78; 95% CI 0.68–0.89), and all-cause death (aHR 0.87; 95% CI 0.81–0.93). Standard-dose NOAC users had a lower risk of ischemic stroke, systemic embolism, and major bleeding events than warfarin users. In contrast, low-dose NOAC users did not differ in risk from warfarin users for all outcomes. In conclusion, NOACs were associated with a lower risk of secondary thromboembolic events and bleeding complications in Korean ischemic stroke patients with NVAF than warfarin.

Abstract 12361: Efficacy and Safety of NOACs vs. Warfarin Across the Continuous Range of Body Mass Index and Body Weight: Insights From COMBINE-AF

Introduction: The efficacy and safety of non-vitamin K oral anticoagulants (NOACs) in patients with atrial fibrillation (AF) at the extremes of body mass index (BMI) and body weight (BW) remains uncertain, leading to concerns regarding use in these populations across clinical practice guidelines. Methods: This analysis of the COMBINE-AF database pools individual patient-level data from the 4 pivotal RCTs of NOAC vs. warfarin in AF: RE-LY, ROCKET-AF, ARISTOTLE, and ENGAGE AF-TIMI 48. Pts randomized to low-dose NOACs not globally approved for clinical use were excluded. The primary efficacy and safety outcome was stroke/systemic embolic event (S/SEE) and major bleeding, respectively, with intracranial hemorrhage (ICH) being a secondary outcome. Outcomes were assessed across BMI and BW using a Cox model stratified by trial, with interaction testing for NOAC vs. warfarin. Restricted cubic splines were used to display the hazard ratio of NOAC vs. warfarin for each outcome across BMI. Results: For 58,464 pts, the median BMI was 28 (25 th -75 th %ile: 25-32) kg/m 2 , with the top 5% (n=2,924) having a BMI ≥ 40 kg/m 2 . For patients randomized to warfarin, the risk of each outcome was lower with increasing BMI (HR per 5 kg/m 2 increase: S/SEE 0.79 [95% CI 0.75-0.84]; major bleeding 0.91 [95% CI 0.87-0.95]; ICH 0.72 [95% CI 0.66-0.80]; p<0.01 for each). There was no significant treatment interaction for NOAC vs. warfarin by BMI for S/SEE (p-interaction = 0.71; Fig 1A ), major bleeding (p-interaction = 0.15; Fig 1B ), or ICH (p-interaction = 0.84; Fig 1C ), such that there was consistent reduction in S/SEE and ICH ( Fig 1A and 1C, respectively ) across the range of BMI with NOAC vs. warfarin. Similar results were seen for each outcome when assessed by BW (median [25 th -75 th %ile]: 81 [70-94] kg; 5 th -95 th %ile: 55-119 kg). Conclusions: In this pooled analysis of the pivotal AF trials, use of NOAC was associated with a consistent reduction in S/SEE and ICH compared with warfarin across the range of BMI and BW.

Oral anticoagulant treatment in patients with atrial fibrillation early after valvular intervention: a nationwide cohort study

Abstract Background Treatment with non-vitamin K oral anticoagulants (NOAC) is the first option for primary prevention of ischaemic stroke in patients with atrial fibrillation (AF). However, there is still an evidence gap regarding efficacy and safety of NOAC in patients with AF and severe valvular heart disease undergoing valvular intervention. Purpose The aim was to evaluate the efficacy and safety of NOAC or no oral anticoagulant (OAC) treatment versus warfarin during the first 3 months after valvular intervention. Methods We used data from the National Quality Register SWEDEHEART and included all patients with AF discharged after surgical valvular intervention with bioprosthesis or valvuloplasty, or transcatheter aortic valve implantation (TAVI) between 2010 and 2016. Outcomes, including the composite of cardiovascular (CV) events (CV death, ischaemic stroke or systemic embolism), major bleeding, and relevant comorbidities and OAC treatment at discharge were collected from the National Patient Register, the Swedish Prescribed Drug Register, and the National Cause of Death Register. The association between exposure (warfarin, NOAC or no OAC) and occurrence of composite CV events and major bleeding was explored using a time-dependent adjusted Cox regression analysis. Results In total, 4730 patients with AF and valvular intervention were included. The cohort had a mean age of 75 years, 35.9% were women and mean CHA2DS2-VASc score was 3.3 (Table 1). The proportion of patients treated with warfarin was higher in patients undergoing surgical valve intervention whereas NOAC was more commonly prescribed to patients treated with TAVI. Rates of composite CV events and major bleeding was similar between patients treated with NOAC versus warfarin. No OAC treatment versus warfarin was associated with higher rate of composite CV event, but with no difference with regard to major bleeding (Table 1). Conclusion A large proportion of patients with AF undergoing valvular intervention was not treated with OAC despite having a high CHA2DS2-VASc score. Also, patients on no OAC versus warfarin had a higher risk of i CV events in the early phase after valvular intervention. The efficacy and safety of NOAC was similar compared to warfarin during the first 3 months after intervention. Treatment with OAC in patients with AF, irrespective of NOAC or warfarin, was associated with improved clinical outcome early after valve intervention. Funding Acknowledgement Type of funding sources: None.

Patients with mild congenital heart defects and atrial arrhythmias: anticoagulate all or follow the CHA2DS2-VASc score?

Abstract Purpose Clinical practice used to anticoagulated all patients with mild congenital heart defects (CHD) and atrial arrhythmias (AA) because of the presence of structural abnormalities. Current guidelines on adult congenital heart disease indicate that in these patients, as per general, the CHA2DS2-VASc score should be followed when deciding upon thromboprophylaxis in case AA. To validate this recommendation, we aimed to assess the incidence of thromboembolism in patients with mild CHD according to CHA2DS2-VASc score using non-vitamin K oral anticoagulants (NOACs) for AA. Methods Data are retrieved from the multinational NOTE-registry, which follows ACHD patients on NOACs for several indications since 2014. Patients in whom NOAC was prescribed for atrial arrhythmias were included in this study. The primary endpoint was the incidence of thromboembolism (TE) and major bleeding (MB). Secondary outcomes were minor bleeding and mortality. Risk stratification was performed using CHA2DS2-VASc score at baseline. Results The NOTE registry has up to date engaged leading ACHD-centers of up to 14 different countries throughout the world, thereby demonstrating a significant effort to fill the gap in science regarding the efficacy and safety of NOACs in the ACHD population. Out of a total of 638 patients, 72 patients had mild congenital defects and NOACs prescribed for AA. The mean age at baseline was 57 (±12) years and 56% was female. Patients were followed up to a maximum of 7 years (202 patient-years; median 2.5, IQR 1.2–4.0). In all patients with a CHA2DS2-VASc score of 0 (n=24), no TE occurred (annualized TE-rate 0%), while 2 patients suffered a MB (annualized MB-rate 3.3%; Figure 1). In patients with a CHA2DS2-VASc score of 1 (n=8) or ≥2 (n=40) the annualized eventrates were 0% and 0.8% for TE, and 0% and 1.7% for MB, respectively. Conclusion These reassuring results demonstrated that the annualized eventrate for TE in patients with mild CHD and a CHA2DS2-VASc score of 0 under treatment with NOACs is very low, at the cost of major bleedings. Following the guidelines seems justified: similar to patients with acquired heart disease the prescription of oral anticoagulant therapy can be refrained from in patients with CHA2DS2-VASc score of 0 and in those with CHA2DS2-VASc score 1 it can be debated weighing the risks and benefits. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Netherlands Heart Institute Figure 1. Eventrates of TE and MB

Non-vitamin K oral anticoagulants versus warfarin for treating left ventricular thrombus

Abstract Background Left ventricular thrombus (LVT) is associated with significant morbidity and mortality. Traditionally treated with anticoagulation by Warfarin, it is unclear if non-vitamin K oral anticoagulants (NOAC) are comparably efficacious and safe. Such data is also scarce in Asian patients. Purpose To compare the clinical efficacy and safety of NOAC with warfarin for managing LVT. Methods Clinical and echocardiographic records of all adult patients with echocardiography-confirmed LVT during January 2011 to January 2020 were retrieved. Any discontinuation of anticoagulation at one year was recorded. Outcomes of patients on NOAC were compared to those on warfarin. The primary outcomes were cumulative mortality and net adverse clinical events (NACE; any of cerebrovascular accident, systemic thromboembolism, intracranial haemorrhage, fatal bleeding, and overt bleeding). Secondary outcomes were complete LVT resolution and percentage reduction in LVT size at three-month follow-up, and the components of NACE. Results In total, 43 patients were included; 28 were treated by warfarin and 15 by NOAC, with mean follow-up periods of 20±12 months and 22±9 months respectively (p=0.522). Significantly fewer NACE were observed in the NOAC cohort (p=0.046; Figure 1), with a trend for lower cumulative mortality (p=0.058; Figure 2). There were no significant differences in the secondary outcomes. Additionally, given resolution of LVT, discontinuation of anticoagulation by one year was not associated with significantly different outcomes. Conclusion NOAC may be an efficacious and safe alternative to warfarin for treating LVT. Further studies are required to confirm our findings and delineate the optimal duration of anticoagulation. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): Hong Kong Special Administrative Region Government Health and Medical Research Fund Figure 1Figure 2

Atrial fibrillation and coronary artery disease: a review on the optimal use of oral anticoagulants.

Atrial fibrillation (AF) represents the most prevalent supraventricular arrhythmia in adults population and up to 15% of AF patients undergo percutaneous coronary intervention (PCI) for coronary artery disease (CAD) during their life. While oral anticoagulants (OACs) exert a protective effect in the setting of stroke prevention and systemic embolization in AF patients, patients undergoing PCI are recommended to receive dual antiplatelet therapy (DAPT) to reduce the risk of cardiovascular death, recurrent myocardial infarction and stent thrombosis. When these two scenarios coexist, as all antithrombotic regimens are burdened by an increase in bleeding risk, antithrombotic regimen and therapy duration must be cautiously tailored on individual patients' characteristics after attentive assessment of ischemic and bleeding risks. Non-vitamin K oral anticoagulants (NOACs), directly inhibiting either thrombin or factor Xa of the coagulation cascade, have progressively replaced warfarin as first choice OACs in several scenarios; recently, randomized controlled trials have compared antithrombotic regimens including NOAC molecules vs vitamin K antagonists in AF patients undergoing PCI to explore the efficacy and safety of NOACs in this setting. These studies have provided a deeper understanding of antithrombotic therapy after PCI in AF patients and have been promptly implemented by the most recent guidelines on AF and CAD management. The aim of the present review was to summarize the current available literature on the perils and benefits of individual OAC molecules in AF patients with acute and/or chronic coronary syndromes in order to provide guidance on the optimal use of OACs in these complex scenarios.

Initial anticoagulation experience with standard-dose rivaroxaban after Watchman left atrial appendage occlusion

Warfarin is now recommended as the standard anti-thrombotic regimen to allow complete endothelialization over the Watchman device post percutaneous left atrial appendage occlusion (LAAO). However, the need for frequent monitoring, narrow therapeutic range, dietary restrictions and multiple drug interactions associated with warfarin have contributed to increasing uptake of non-vitamin K oral anticoagulants (NOACs) worldwide. At present, the feasibility and safety of NOACs instead of warfarin post-LAAO is lacking. Patients who underwent successful Watchman device implantation between October 1, 2016 and September 30, 2017 were enrolled in a retrospective database. And only patients who received rivaroxaban in the periprocedural period were included in this study. Transesophageal echocardiography (TEE) follow-up was scheduled at 6 weeks, at 6 months, and at 12 months post-implantation to detect device-related thrombosis (DRT) or peri-device leak. Meanwhile, thromboembolic and bleeding events were also evaluated at the time of follow-up. Totally, 57 Watchman devices were successfully implanted and 10 patients who were allocated to rivaroxaban at the dosage of 20 mg once daily were included. During the follow-up, none of the patients using rivaroxaban experienced DRT, peri-device leak, thromboembolic complications and major bleeding events, except for 2 patients who suffered minor bleeding during the 6 weeks follow-up. This study suggests that a short course of standard-dose rivaroxaban following Watchman LAAO is associated with low incidence of thrombotic complications and bleeding events, and might be a feasible alternative regimen in Chinese. Further randomized trials and large sample of real-world studies are needed to validate our finding.

6072Risk of stroke in hypertensive patients with atrial fibrillation treated with oral anticoagulants

Abstract Background Hypertension is common in patients with atrial fibrillation (AF) and carries an additional risk for complications, most notably stroke and bleeding. We assessed the history of hypertension, level of blood pressure control, and an interaction with the choice of oral anticoagulants on clinical outcomes. Purpose To gain insights into the risks of hypertension in the setting of AF and explore possible interactions with the safety and efficacy of non-vitamin K oral anticoagulants (NOACs) versus vitamin K antagonists (VKAs). Methods We performed a systematic review and meta-analysis of studies that randomised patients to NOACs or VKAs and reported outcomes stratified by presence of hypertension. Collected outcomes included: ischaemic stroke or systemic embolism (SE), death from any cause, hemorrhagic stroke, major bleeding, and intracranial hemorrhage. Log adjusted hazard ratios (HR) and corresponding standard error were calculated, and HRs were compared using Mantel-Haenszel random effects. Quality of the evidence was assessed with Cochrane risk of bias tool. Results Five high-quality studies were eligible, including 71,602 participants who received NOACs (apixaban, dabigatran, edoxaban, rivaroxaban) or VKAs, with median follow-up of 1.8–2.8 years. 89.2% of participants had a history of hypertension. Compared with patients without hypertension, those with controlled and uncontrolled hypertension had higher risk for stroke/SE (HR: 1.21 [1.04–1.41] and HR: 1.50 [1.12–2.01], respectively) and haemorrhagic stroke (HR: 1.78 [1.06, 3.00] and HR: 1.66 [0.99–4.01], respectively). On a continuous scale, the risk of stroke increased 7% per 10mmHg increase in systolic blood pressure. As shown in the Table, no interactions were found between hypertension status and the efficacy or safety of NOACs versus VKAs. Table 1. Interaction of presence of hypertension on the comparative efficacy and safety of NOAC versus VKA Hypertension (n=63,869) No hypertension (n=7,733) P-value (int) Adjusted HR, 95% CI Adjusted HR, 95% CI Stroke or systemic embolism 080, 0.72–0.89 0.79, 0.53–1.19 0.98 Haemorrhagic stroke 0.55, 0.41–0.74 0.24, 0.04–1.37 0.36 Death from any cause 0.91, 0.84–0.98 0.89, 0.76–1.04 0.82 Major bleeding 0.90, 0.76–1.07 0.84, 0.69–1.01 0.57 Intracranial haemorrhage 0.41, 0.24-.068 0.48, 0.14–1.69 0.81 Major or clinically relevant non-major bleed 0.90, 0.68–1.18 0.91, 0.55–1.53 0.96 Conclusions Adequate blood pressure management is vital to optimally reduce the risk of stroke in patients with atrial fibrillation. The benefits of NOACs over VKAs, also apply to patients with elevated blood pressure.

3054Efficacy and safety of non-vitamin K oral anticoagulants in patients with atrial fibrillation and cancer

Abstract Background Anticoagulation in patients with cancer and atrial fibrillation (AF) is particularly challenging given the higher risk of both thrombotic and bleeding complications in this setting. Data regarding the efficacy and safety of non-vitamin K oral anticoagulants (NOACs) in AF patients with malignancy remain unclear. Purpose In the present meta-analysis we further investigate the efficacy and safety of NOACs compared to warfarin in patients with AF and cancer assuming that available studies may be individually underpowered for endpoints at low incidence, i.e. stroke, major and intracranial bleeding. Methods We performed a systematic review and meta-analysis of studies comparing the use of NOACs vs. warfarin in AF patients with cancer. Efficacy outcome measures included stroke or systemic embolism, venous thromboembolism and mortality. Safety outcome measures were major bleeding and intracranial hemorrhage. Results We pooled data from 6 identified studies enrolling a total of 31,756 AF patients with cancer. Mean follow-up was 1.7 years. Patients with cancer had significantly increased annualized rates of venous thromboembolism (1.38% vs. 0.74%), major bleeding (9.01% vs. 5.13%), in particular major gastrointestinal bleeding (2.38% vs. 1.60%), and all-cause mortality (17.73% vs. 8.50%) vs. those without (all P values <0.001), whereas the incidence of stroke or systemic embolism and intracranial hemorrhage did not differ. Compared with warfarin, treatment with NOACs nominally decreased the risk of stroke or systemic embolism (5.41% vs. 2.70%; odds ratio, OR; 95% confidence intervals, CI 0.51, 0.26–1.01; P=0.05; Figure), mainly of ischemic stroke (OR 0.56; 95% CI 0.35–0.89; P=0.01), and the risk of venous thromboembolism (OR 0.51; 95% CI 0.42–0.61; P<0.001). In cancer patients receiving NOACs there was a significant reduction of major bleeding (3.95% vs. 4.66%; OR 0.66, 95% CI 0.46–0.94; P=0.02; Figure) and intracranial hemorrhage (0.26% vs. 0.66%; OR 0.25, 95% CI 0.08–0.82; P=0.02) vs. warfarin, with no difference in gastrointestinal major bleeding rates. Conclusion AF patients on oral anticoagulation and concomitant cancer are at higher risk of venous thromboembolism, major bleeding and all-cause mortality. NOACs may represent a safer and more effective alternative to warfarin also in this setting of patients.

Safety of concomitant treatment with Non-Vitamin K Oral Anticoagulants and SSRI/SNRI antidepressants

Introduction: Warfarin has been considered as a “gold standard” in the prevention and treatment of thromboembolic events since 1954. Since the introduction of direct oral anticoagulants in the last few years (NOAC-Non-Vitamin K antagonist Oral Anticoagulants) prescriptions volume for apixaban, edoxaban, dabigatran and rivaroxaban have been gradually surpassing warfarin. The benefits include: anticoagulation from day one, fixed daily dosing, elimination for the need of international normalised ratio (INR) monitoring, fewer interactions with food and co-administered medicines with reduced risk of bleeding and better overall life quality. Objectives: Assessing evidence for the safe use of Non-vitamin K Oral Anticoagulants (NOAC) with Selective Serotonin Reuptake Inhibitors (SSRI) and Serotonin and Noradrenaline Reuptake Inhibitors (SNRI). Method: Review of literature published between 2014 and 2016 was made using the key words: Selective Serotonin Reuptake Inhibitor, Serotonin and Noradrenaline Reuptake Inhibitors, apixaban, dabigatran, edoxaban, rivaroxaban, bleeding, interaction, depression with time description from 2014 to 2018. Evidence within the literature was then compared with guidelines from the National Institute for Health and Care Excellence (UK), British National Formulary (UK), Clinical Excellence Commission (Australia), Thrombophilia and Anticoagulation Clinic (USA) and Summaries of Product Characteristics (SPC). Results: 1. Serotonin plays a critical role in maintaining homeostasis. Use of SSRI/SNRI compromises its platelet reuptake increasing risk of bleeding. 2. Increased tolerability and safety of NOAC over Warfarin, although caution is advised when NOAC is used with SSRI/SNRI with less evidence suggesting pharmacodynamic interactions. 3. It is not recommended to use NOAC with strong CYP and P-gp inhibitors. Conclusions: With limited literature evidence, caution is advised when co-prescribed NOACs with SSRI/SNRI, especially with other cofactors and interacting medicines further increasing risk of bleeding. Keywords: SSRI, SNRI, NOAC, risk of bleeding, drug interactions