HEMATURIA AND OTHER KINDS OF BLEEDINGS ON NON-VITAMIN K ANTAGONIST ORAL ANTICOAGULANTS IN PATIENTS WITH ATRIAL FIBRILLATION: AN UPDATED OVERVIEW ON OCCURRENCE, PATHOMECHANISMS AND MANAGEMENT

Non-vitamin K antagonist oral anticoagulants (NOACs) are currently recommended for oral anticoagulation in patients with non-valvular atrial fibrillation. In the setting, NOACs effectively prevent from stroke and systemic embolic events. In spite of the favorable safety profile of NOACs when compared with vitamin K antagonists, the use of any kind of anticoagulation is associated with an increased risk of bleeding. However, there is still a lack of direct comparisons of effectiveness and safety among NOACs. The results of indirect comparisons and meta-analyses suggest that the risk of various types of hemorrhagic complications differ among the particular NOACs. Management of bleeding in patients under NOAC therapy can be challenging because of limited availability of antidotes and the lack of routine laboratory test monitoring the NOAC anticoagulant effect. In case of life-threatening or critical site bleeding, reversal of NOAC anticoagulant activity is essential together with immediate implementation of causative treatment. Moreover, some patients on chronic NOAC therapy may require urgent surgery or invasive procedures. Specific reversal agents for NOACs have been developed, i.e. more widely available idarucizumab for the factor IIa inhibitor (dabigatran) and andexanet alfa for the factor Xa inhibitors (rivaroxaban, apixaban, edoxaban) with limited availability. This review summarizes the occurrence and management of NOAC-related bleeding complications with a particular emphasis on hematuria.

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Selection, management, and outcome of vitamin K antagonist-treated patients with atrial fibrillation not switched to novel oral anticoagulants

Thrombosis and Haemostasis ◽

10.1160/th15-02-0116 ◽

2015 ◽

Vol 114 (11) ◽

pp. 1076-1084 ◽

Cited By ~ 15

Author(s):

Franziska Michalski ◽

Luise Tittl ◽

Sebastian Werth ◽

Ulrike Hänsel ◽

Sven Pannach ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Case Fatality ◽

Bleeding Risk ◽

Vitamin K Antagonist ◽

Bleeding Complications ◽

Treatment Rate

SummaryAtrial fibrillation (AF) patients treated with well-controlled vitamin K antagonists (VKAs) may benefit less from non-vitamin K antagonist oral anticoagulants (NOACs) because they are supposed to be at low risk of thromboembolic and bleeding complications. However, little is known about the selection, management, and outcome of such “stable” VKA patients in current practice. We assessed characteristics, VKA persistence and 12 months' outcome of AF patients selected for VKA continuation. On March 1, 2013, the Dresden NOAC registry opened recruitment of patients continuing on VKA for sites that had been actively recruiting AF patients treated with NOACs in the prior 18 months. Patient characteristics were compared with those of NOAC patients from the same sites. Four hundred twenty-seven VKA patients had a significantly lower bleeding risk profile compared with 706 patients selected for NOAC treatment. For VKA, international normalised ratio time-in-therapeutic range before enrolment was 71% and increased to 75% during a mean follow-up of 15 months. Rates of stroke/transient ischaemic attack/systemic embolism were 1.3/100 patient-years (intention-to-treat) and 0.94/100 patient-years (as-treated). On-treatment rate of ISTH major bleeding was 4.15/100 patient-years (95% CI 2.60–6.29) with a case-fatality rate of 16.3% (all-cause mortality at day 90 after major bleeding). In conclusion, in daily care, AF patients selected for VKA therapy are healthier than those treated with NOAC, demonstrate a high quality of anticoagulant control and very low stroke rates. However, despite adequate patient selection and INR control, the risk of major VKA bleeding is unacceptably high and bleeding outcome is poor.

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Overcoming global challenges in stroke prophylaxis in atrial fibrillation: The role of non-vitamin K antagonist oral anticoagulants

International Journal of Stroke ◽

10.1177/1747493016660106 ◽

2016 ◽

Vol 11 (9) ◽

pp. 950-967 ◽

Cited By ~ 2

Author(s):

Ayrton Massaro ◽

Robert P Giugliano ◽

Bo Norrving ◽

Ali Oto ◽

Roland Veltkamp

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Health Care Systems ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Ageing Population ◽

Maximum Benefit ◽

Increased Risk ◽

Care Systems

Atrial fibrillation is the world's most common sustained cardiac arrhythmia and is associated with a significantly increased risk of stroke. The global burden of atrial fibrillation is rising, commensurate with the ageing population. Well-controlled vitamin K antagonist-based anticoagulation has been shown to reduce the risk of stroke secondary to atrial fibrillation by two-thirds. However, patients with atrial fibrillation have frequently been denied anticoagulation because of a variety of perceived risks related to bleeding, falls, chronological age, and poor compliance. Even when vitamin K antagonists are used, maximum benefit and safety are only delivered when high quality control of therapy (TTR > 70%) is achieved, which has proven remarkably difficult in many health-care systems and amongst many patient groups. The non-vitamin K antagonist oral anticoagulants (NOACs) offer solutions to many of the challenges of achieving widespread, safe, and effective anticoagulation for stroke prophylaxis in atrial fibrillation, yet their uptake into routine clinical practice remains variable. The evidence supporting their more widespread use to overcome the challenges of stroke prophylaxis for atrial fibrillation is reviewed in this article.

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The Risk of Gastrointestinal Bleeding between Non-Vitamin K Antagonist Oral Anticoagulants and Vitamin K Antagonists in the Asian Atrial Fibrillation Patients: A Meta-Analysis

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18010137 ◽

2020 ◽

Vol 18 (1) ◽

pp. 137

Author(s):

Kuang-Tsu Yang ◽

Wei-Chih Sun ◽

Tzung-Jiun Tsai ◽

Feng-Woei Tsay ◽

Wen-Chi Chen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Gastrointestinal Bleeding ◽

Vitamin K ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

Cochrane Library ◽

Secondary Outcome ◽

Optimal Dosage

Background: Non-vitamin K antagonist oral anticoagulants (NOACs) are more commonly used to prevent atrial fibrillation (AF) patients from thromboembolic events than vitamin K antagonists (VKAs). However, the gastrointestinal bleeding (GIB) risk in the Asian AF patients associated with NOACs in comparison with VKAs remained unaddressed. Materials and Methods: A systematic search of studies on NOACs and VKAs in the Asian AF patients was conducted in PubMed, Cochrane Library, and ClinicalTrials.gov. The primary outcome was the hazard ratio (HR) of any GIB associated with NOACs versus VKAs. The secondary outcome was the GIB risks in different kinds of NOACs compared with VKAs. Results: This meta-analysis included two randomized controlled trials (RCTs) and four retrospective studies, comprising at least 200,000 patients in total. A significantly lower HR of GIB risks was found in all kinds of NOACs than VKAs in the Asian AF patients (HR: 0.633; 95% confidence interval: 0.535–0.748; p < 0.001). Additionally, the GIB risks of different NOACs were apixaban (HR: 0.392), edoxaban (HR: 0.603), dabigatran (HR: 0.685), and rivaroxaban (HR: 0.794), respectively. Conclusions: NOACs significantly reduced the risk of GIB in the Asian AF patients compared with VKAs. In the four NOACs compared with VKAs, apixaban probably had a trend of the least GIB risk. We need further head-to-head studies of different NOACs to confirm which NOAC is the most suitable for Asian AF patients and to know the optimal dosage regimen of different NOACs.

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Non–Vitamin K Antagonist Oral Anticoagulants in the Treatment of Atrial Fibrillation

Annual Review of Medicine ◽

10.1146/annurev-med-042617-092334 ◽

2019 ◽

Vol 70 (1) ◽

pp. 61-75 ◽

Cited By ~ 3

Author(s):

Alexander C. Fanaroff ◽

E. Magnus Ohman

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Major Bleeding ◽

Anticoagulant Activity ◽

Oral Anticoagulants ◽

Significant Risk ◽

Vitamin K Antagonist ◽

Therapeutic Window ◽

Mechanical Valves ◽

Frequent Monitoring

Atrial fibrillation (AF) increases a patient's stroke risk four- to five-fold. Anticoagulation with the vitamin K antagonist (VKA) warfarin reduces the risk of stroke by 67%, but warfarin carries a significant risk of major bleeding and has unpredictable pharmacodynamics with a narrow therapeutic window, necessitating frequent monitoring of its anticoagulant effect. The non–vitamin K antagonist oral anticoagulants (NOACs) dabigatran, rivaroxaban, apixaban, and edoxaban provide more predictable anticoagulant activity than warfarin with a lower risk of major bleeding, and each is noninferior to warfarin for the prevention of stroke. All have earned regulatory approval in the past eight years. At least one of the NOACs is approved for use in all patients with AF, except those with mechanical valves and rheumatic mitral valve disease, for whom warfarin remains the only option. Recent clinical trials have shown that antithrombotic regimens including NOACs are safe and effective in patients with AF who need potent antiplatelet therapy.

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Optimal Anticoagulation Strategy for Cardioversion in Atrial Fibrillation

Arrhythmia & Electrophysiology Review ◽

10.15420/aer.2015.4.1.44 ◽

2015 ◽

Vol 4 (1) ◽

pp. 44 ◽

Cited By ~ 2

Author(s):

Philipp Bushoven ◽

Sven Linzbach ◽

Mate Vamos ◽

Stefan H Hohnloser ◽

◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Stroke Prevention ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Prospective Trial ◽

Bleeding Complications ◽

Order Of Magnitude ◽

Pharmacological Cardioversion

For many patients with symptomatic atrial fibrillation, cardioversion is performed to restore sinus rhythm and relieve symptoms. Cardioversion carries a distinct risk for thromboembolism which has been described to be in the order of magnitude of 1 to 3 %. For almost five decades, vitamin K antagonist therapy has been the mainstay of therapy to prevent thromboembolism around the time of cardioversion although not a single prospective trial has formally established its efficacy and safety. Currently, three new direct oral anticoagulants are approved for stroke prevention in patients with non-valvular atrial fibrillation. For all three, there are data regarding its usefulness during the time of electrical or pharmacological cardioversion. Due to the ease of handling, their efficacy regarding stroke prevention, and their safety with respect to bleeding complications, the new direct oral anticoagulants are endorsed as the preferred therapy over vitamin K antagonists for stroke prevention in non-valvular atrial fibrillation including the clinical setting of elective cardioversion.

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New Oral Anticoagulants vs. Vitamin K Antagonists Among Patients With Cardiac Amyloidosis: Prognostic Impact

Frontiers in Cardiovascular Medicine ◽

10.3389/fcvm.2021.742428 ◽

2021 ◽

Vol 8 ◽

Author(s):

Eve Cariou ◽

Kevin Sanchis ◽

Khailène Rguez ◽

Virginie Blanchard ◽

Stephanie Cazalbou ◽

...

Keyword(s):

Vitamin K ◽

Cardiac Amyloidosis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Bleeding Complications ◽

Prognostic Impact ◽

Transthyretin Amyloidosis ◽

Increased Risk ◽

All Cause Mortality ◽

History Of

Background: Atrial arrhythmia (AA) is common among patients with cardiac amyloidosis (CA), who have an increased risk of intracardiac thrombus. The aim of this study was to explore the prognostic impact of vitamin K-antagonists (VKA) and direct oral anticoagulants (DOAC) in patients with CA.Methods and Results: 273 patients with CA and history of AA with long term anticoagulation−69 (25%) light chain amyloidosis (AL), 179 (66%) wild-type transthyretin amyloidosis (ATTRwt) and 25 (9%) variant transthyretin amyloidosis (ATTRv)–were retrospectively included between January 2012 and July 2020. 147 (54%) and 126 (46%) patients received VKA and DOAC, respectively. Patient receiving VKA were more likely to have AL with renal dysfunction, higher NT-proBNP and troponin levels. Patients with ATTRwt were more likely to receive DOAC therapy. There were more bleeding complications among patients with VKA (20 versus 10%; P = 0.013) but no difference for stroke events (4 vs. 2%; P = 0.223), as compared to patients with DOAC. A total of 124 (45%) patients met the primary endpoint of all-cause mortality: 96 (65%) and 28 (22%) among patients with VKAs and DOACs, respectively (P < 0.001). After multivariate analysis including age and renal function, VKA was no longer associated with all-cause mortality.Conclusion: Among patients with CA and history of AA receiving oral anticoagulant, DOACs appear to be at least as effective and safe as VKAs.

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The NOACs: clinical pharmacology

ESC CardioMed ◽

10.1093/med/9780198784906.003.0056 ◽

2018 ◽

pp. 268-272

Author(s):

Jeffrey Weitz

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Active Site ◽

Randomized Clinical Trials ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Factor Xa ◽

Vitamin K Antagonist ◽

Phase Iii ◽

High Affinity

The limitations of vitamin K antagonists prompted the development of new oral anticoagulants that could be administered in fixed doses without routine coagulation monitoring. Focusing on thrombin and factor Xa because of their prominent roles in coagulation, structure-based design led to the development of small molecules that bind to the active site pockets of these enzymes with high affinity and specificity. Four non-vitamin K antagonist oral anticoagulants are now licensed: dabigatran, which inhibits thrombin, and rivaroxaban, apixaban, and edoxaban, which inhibit factor Xa. In phase III randomized clinical trials that included over 100,000 patients these agents have proven to be at least as effective as vitamin K antagonists for prevention of stroke in patients with non-valvular atrial fibrillation and for treatment of venous thromboembolism, and to produce less bleeding, particularly less intracranial bleeding.

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Non-vitamin K antagonist oral anticoagulants vs. vitamin-K antagonists in patients with atrial fibrillation and chronic kidney disease: a nationwide cohort study

Thrombosis Journal ◽

10.1186/s12959-019-0211-y ◽

2019 ◽

Vol 17 (1) ◽

Cited By ~ 2

Author(s):

Emma Kirstine Laugesen ◽

Laila Staerk ◽

Nicholas Carlson ◽

Anne-Lise Kamper ◽

Jonas Bjerring Olesen ◽

...

Keyword(s):

Atrial Fibrillation ◽

Chronic Kidney Disease ◽

Kidney Disease ◽

Vitamin K ◽

Major Bleeding ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Vitamin K Antagonist ◽

All Cause Mortality ◽

Comparable Population

Abstract Background We aimed to compare effectiveness and safety of non-vitamin K antagonist oral anticoagulants (NOACs) versus vitamin-K antagonists (VKA) in atrial fibrillation (AF) patients with chronic kidney disease (CKD) not receiving dialysis. Methods By using personal identification numbers, we cross-linked individual-level data from Danish administrative registries. We identified every citizen with a prior diagnosis of AF and CKD who initiated NOAC or VKA (2011–2017). An external analysis of 727 AF patients with CKD (no dialysis) was performed to demonstrate level of kidney function in a comparable population. Study outcomes included incidents of stroke/thromboembolisms (TEs), major bleedings, myocardial infarctions (MIs), and all-cause mortality. We used Cox proportional hazards models to determine associations between oral anticoagulant treatment and outcomes. Results Of 1560 patients included, 1008 (64.6%) initiated VKA and 552 (35.4%) initiated NOAC. In a comparable population we found that 95.3% of the patients had an estimated glomerular filtration rate (eGFR) < 59 mL/min. Patients treated with NOAC had a significantly decreased risk of major bleeding (hazard ratio (HR): 0.47, 95% confidence interval (CI): 0.26–0.84) compared to VKA. There was not found a significant association between type of anticoagulant and risk of stroke/TE (HR: 0.83, 95% CI: 0.39–1.78), MI (HR: 0.45, 95% CI: 0.18–1.11), or all-cause mortality (HR: 0.99, 95% CI: 0.77–1.26). Conclusion NOAC was associated with a lower risk of major bleeding in patients with AF and CKD compared to VKA. No difference was found in risk of stroke/TE, MI, and all-cause mortality.

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Direct oral anticoagulants versus vitamin K antagonists in patients with atrial fibrillation and cancer a meta-analysis

Journal of Thrombosis and Thrombolysis ◽

10.1007/s11239-020-02304-3 ◽

2020 ◽

Cited By ~ 2

Author(s):

Marco Valerio Mariani ◽

Michele Magnocavallo ◽

Martina Straito ◽

Agostino Piro ◽

Paolo Severino ◽

...

Keyword(s):

Atrial Fibrillation ◽

Vitamin K ◽

Major Bleeding ◽

Meta Analysis ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Significant Risk ◽

Bleeding Complications ◽

Efficacy And Safety

Abstract Background Direct oral anticoagulants (DOACs) are recommended as first-line anticoagulants in patients with atrial fibrillation (AF). However, in patients with cancer and AF the efficacy and safety of DOACs are not well established. Objective We performed a meta-analysis comparing available data regarding the efficacy and safety of DOACs vs vitamin K antagonists (VKAs) in cancer patients with non-valvular AF. Methods An online search of Pubmed and EMBASE libraries (from inception to May, 1 2020) was performed, in addition to manual screening. Nine studies were considered eligible for the meta-analysis involving 46,424 DOACs users and 182,797 VKA users. Results The use of DOACs was associated with reduced risks of systemic embolism or any stroke (RR 0.65; 95% CI 0.52–0.81; p 0.001), ischemic stroke (RR 0.84; 95% CI 0.74–0.95; p 0.007) and hemorrhagic stroke (RR 0.61; 95% CI 0.52–0.71; p 0.00001) as compared to VKA group. DOAC use was associated with significantly reduced risks of major bleeding (RR 0.68; 95% CI 0.50–0.92; p 0.01) and intracranial or gastrointestinal bleeding (RR 0.64; 95% CI 0.47–0.88; p 0.006). Compared to VKA, DOACs provided a non-statistically significant risk reduction of the outcomes major bleeding or non-major clinically relevant bleeding (RR 0.94; 95% CI 0.78–1.13; p 0.50) and any bleeding (RR 0.91; 95% CI 0.78–1.06; p 0.24). Conclusions In comparison to VKA, DOACs were associated with a significant reduction of the rates of thromboembolic events and major bleeding complications in patients with AF and cancer. Further studies are needed to confirm our results.

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