Bleeding Complication in a Patient with Concomitant Use of Rivaroxaban and Saffron Supplement: A Case Report

Abstract Background Direct oral anticoagulants (DOACs) carry a lower potential risk of food/herb and drug interactions compared with oral vitamin K antagonists. However, as a new class of medications some of these interactions have not been fully known. Case presentation: A 64-year old male with a medical history of non-valvular atrial fibrillation presented to the emergency department with a complaint of acute onset epistaxis and bleeding gums following the concomitant use of rivaroxaban and saffron supplement. Rivaroxaban plasma concentration was 54 ng/ml with a post-intake delay of 17 hours. The results of laboratory tests were unremarkable except for platelet function tests. Whole blood multiple electrode aggregometry was performed to assess platelet function. Area under the aggregation curve (AUC) values were 83 and 51 aggregation unit (AU)*min by arachidonic acid and adenosine diphosphate-induced platelet aggregation tests, respectively. As the patient had not taken any antiplatelet medication, platelet dysfunction was greatly attributed to the saffron supplement. The patient was immediately admitted to hospital and received local hemostatic measures and tranexamic acid. Moreover, saffron was discontinued permanently and rivaroxaban was paused for 24 hours. The bleeding stopped a few hours later and the patient was discharged after 2 days in a good general condition. Subsequently, he was followed up at 4, 8, and 12-week intervals. He was in a stable clinical condition with no bleeding complications. The patient was advised to consult with his doctor or pharmacist before taking any supplement or herbal medicine to ensure possible interactions. Conclusions It seems that coadministration of DOACs and saffron supplements should be avoided due to the potential drug-herbal interactions and possible risk of subsequent bleeding complications. However, further studies are needed to confirm the findings and assess the clinical significance.

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Falls in ED patients: do elderly patients on direct oral anticoagulants bleed less than those on vitamin K antagonists?

Scandinavian Journal of Trauma Resuscitation and Emergency Medicine ◽

10.1186/s13049-021-00866-6 ◽

2021 ◽

Vol 29 (1) ◽

Author(s):

Martin Müller ◽

Ioannis Chanias ◽

Michael Nagler ◽

Aristomenis K. Exadaktylos ◽

Thomas C. Sauter

Keyword(s):

Elderly Patients ◽

Vitamin K ◽

Intracranial Haemorrhage ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Complications ◽

Lower Odds ◽

Anticoagulated Patients ◽

Proportional Incidence

Abstract Background Falls from standing are common in the elderly and are associated with a significant risk of bleeding. We have compared the proportional incidence of bleeding complications in patients on either direct oral anticoagulants (DOAC) or vitamin K antagonists (VKA). Methods Our retrospective cohort study compared elderly patients (≥65 years) on DOAC or VKA oral anticoagulation who presented at the study site – a Swiss university emergency department (ED) – between 01.06.2012 and 01.07.2017 after a fall. The outcomes were the proportional incidence of any bleeding complication and its components (e.g. intracranial haemorrhage), as well as procedural and clinical parameters (length of hospital stay, admission to intensive care unit, in-hospital-mortality). Uni- and multivariable analyses were used to compare the studied outcomes. Results In total, 1447 anticoagulated patients were included – on either VKA (n = 1021) or DOAC (n = 426). There were relatively more bleeding complications in the VKA group (n = 237, 23.2%) than in the DOAC group (n = 69, 16.2%, p = 0.003). The difference persisted in multivariable analysis with 0.7-fold (95% CI: 0.5–0.9, p = 0.014) lower odds for patients under DOAC than under VKA for presenting with any bleeding complications, and 0.6-fold (95% 0.4–0.9, p = 0.013) lower odds for presenting with intracranial haemorrhage. There were no significant differences in the other studied outcomes. Conclusions Among elderly, anticoagulated patients who had fallen from standing, those under DOACs had a lower proportional incidence of bleeding complications in general and an even lower incidence of intracranial haemorrhage than in patients under VKAs.

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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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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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The Effectiveness and Safety of Direct Oral Anticoagulants (DOACs) Vs. Traditional Anticoagulants in Patients with Cirrhosis

Blood ◽

10.1182/blood.v128.22.5015.5015 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5015-5015

Author(s):

Justin Hum ◽

Janice Jou ◽

Thomas G. Deloughery ◽

Joseph Shatzel

Keyword(s):

Major Bleeding ◽

Conflicts Of Interest ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Complications ◽

Efficacy And Safety ◽

Recurrent Thrombosis ◽

Bleeding Events ◽

Cirrhotic Patients

Abstract Introduction: The coagulopathy associated with cirrhosis is complex and places patients at risk for both bleeding and thrombosis. Direct oral anticoagulants (DOACs) have been shown to have superior efficacy and safety compared to vitamin K antagonists; however their efficacy and safety in cirrhotic patients is not clear. The aim of this study is to retrospectively compare the effectiveness and bleeding complications of DOACs as compared to traditional anticoagulants in cirrhotic patients. Methods: This study was a retrospective review of patients treated at a single academic center between 2012-2015 who were prescribed a DOAC (apixaban or rivaroxaban), or a traditional anticoagulant (warfarin or low molecular weight heparin), with an ICD-9 code for the diagnosis of cirrhosis. The primary outcomes of interest are recurrent thrombosis or stroke (efficacy failure), or bleeding events (safety failure). Major bleeds were characterized as fatal bleeding, symptomatic bleeding in critical organ area, or bleeding causing a fall in hemoglobin level >2 or leading to transfusion of 2+ units of packed red blood cells. Results: During the study period, 27 cirrhotic patients were prescribed a DOAC and 18 were prescribed a traditional anticoagulant (either LMWH or warfarin). Both groups had similar total bleeding events (8 DOAC vs. 10 traditional anticoagulation, p = 0.12). There were significantly less major bleeding episodes in the DOAC group, (1 (4%) vs. 5 (28%), p = 0.03) and less intracranial bleeding (3 (17% ) vs. 0 (0%) p=0.06). Recurrent thrombosis or stroke occurred in 1 (4%) patient in the DOAC group and 1 (6%) patient in the traditional group (p = 1.0). Conclusions: Anticoagulation with DOACs in cirrhotic patients may be as safe as traditional anticoagulants with respect to bleeding events. Patients with cirrhosis at our center prescribed DOACs had less major bleeding events, while maintaining efficacy at preventing stroke or recurrent thrombosis. Table Table. Disclosures No relevant conflicts of interest to declare.

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Safety and Feasibility of Treatment with Rivaroxaban in Children for Non-Routine Indications: A Case Series Analysis

Blood ◽

10.1182/blood.v128.22.5014.5014 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5014-5014 ◽

Cited By ~ 1

Author(s):

Kathryn E. Dickerson ◽

Ravi Sarode ◽

Ayesha Zia

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Anticoagulation Therapy ◽

Case Series ◽

Bleeding Complications ◽

Fixed Dose ◽

The Mean ◽

Recurrent Vte

Background. Anticoagulation therapy is the cornerstone of acute treatment of venous thromboembolism (VTE) and for prevention of recurrent VTE. The need for anticoagulation is increasing in children, largely in part due to increasing VTE rates. Conventional anticoagulants, including heparin, low-molecular weight heparins (LMWH), Fondaparinux, and vitamin K antagonists (VKA) are widely used in children but have limitations. Standard of care management with these agents is plagued with the trade-off between daily or twice daily injections or frequent monitoring of therapeutic effect. The advent of direct oral anticoagulants (DOACs) have catalyzed significant changes in the therapeutic landscape of VTE management. DOACs have been evaluated for safety and efficacy in large, randomized controlled trials in the treatment and prevention of VTE in adults, with results that are comparable to conventional therapy. None of the current DOACs have FDA-approved indications and dosing in children yet. Off-label use of these agents is largely based on adult data and doses, and is increasing at many Children's Hospitals across US. Rivaroxaban, a DOAC, is a factor Xa inhibitor with predictable pharmacokinetic and pharmacodynamics properties. Methods. We describe a case series of 8 unique pediatric cases, treated with Rivaroxaban, for a variety of non-routine indications, due either to adverse effects, intolerability of LMWH or VKA or the need for ongoing, long term anticoagulation. Rivaroxaban was started after informed consent and assent from parents or patients respectively, and was initiated at a fixed dose but titrated to a final dose after monitoring of trough and peak Rivaroxaban levels (Aniara, West Chester,OH, USA). Results. The mean age of patients in this case series is 14 years (median: 16, range 3-17) (see Table). The most common indication to use Rivaroxaban was the need for long term anticoagulation after having completed therapeutic anticoagulation, except in two patients, one of whom developed warfarin skin necrosis due to protein C deficiency and another with heparin induced thrombocytopenia. Only two patients needed dose adjustments to achieve target trough and peak drug levels. The mean duration of follow-up is 9 months (median= 5.5; range 3-24) (see Table) at this time. None of the patients developed recurrent VTE while on Rivaroxaban. A soft tissue traumatic bleed occurred in one patient which was treated with holding off the drug for 48 hours. No other bleeding complications were observed. Conclusions. Clinical application of DOACs in a real world clinical setting, including strong thrombophilia and malignancy, results in treatment profile of high efficacy and safety in children; however, larger studies are needed to validate these findings. Disclosures Sarode: CSL Behring: Consultancy, Honoraria.

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Has the introduction of direct oral anticoagulants (DOACs) in England increased emergency admissions for bleeding conditions? A longitudinal ecological study

BMJ Open ◽

10.1136/bmjopen-2019-033357 ◽

2020 ◽

Vol 10 (5) ◽

pp. e033357 ◽

Cited By ~ 2

Author(s):

Ana Alfirevic ◽

Jennifer Downing ◽

Konstantinos Daras ◽

Terence Comerford ◽

Munir Pirmohamed ◽

...

Keyword(s):

Ecological Study ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Emergency Admission ◽

Bleeding Complications ◽

Annual Number ◽

Emergency Admissions ◽

Admission Rates ◽

Complications Rate

ObjectiveThere is concern about long-term safety of direct oral coagulants (DOACs) in clinical practice. Our aim was to investigate whether the introduction of DOACs compared with vitamin-K antagonists in England was associated with a change in admissions for bleeding or thromboembolic complications.Setting5508 General practitioner (GP) practices in England between 2011 and 2016.ParticipantsAll GP practices in England with a registered population size of greater than 1000 that had data for all 6 years.Main outcome measureThe rate of emergency admissions to hospital for bleeding or thromboembolism, per 100 000 population for each GP practice in England.Main exposure measureThe annual number of DOAC items prescribed for each GP practice population as a proportion of all anticoagulant items prescribed.DesignThis longitudinal ecological study used panel regression models to investigate the association between trends in DOAC prescribing within GP practice populations and trends in emergency admission rates for bleeding and thromboembolic conditions, while controlling for confounders.ResultsFor each additional 10% of DOACs prescribed as a proportion of all anticoagulants, there was a 0.9% increase in bleeding complications (rate ratio 1.008 95% CI 1.003 to 1.013). The introduction of DOACs between 2011 and 2016 was associated with additional 4929 (95% CI 2489 to 7370) emergency admissions for bleeding complications. Increased DOAC prescribing was associated with a slight decline in admission for thromboembolic conditions.ConclusionOur data show that the rapid increase in prescribing of DOACs after changes in National Institute for Health and Care Excellence guidelines in 2014 may have been associated with a higher rate of emergency admissions for bleeding conditions. These consequences need to be considered in assessing the benefits and costs of the widespread use of DOACs.

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Reversal strategies in patients treated with direct oral anticoagulants

VASA ◽

10.1024/0301-1526/a000777 ◽

2019 ◽

Vol 48 (5) ◽

pp. 389-392 ◽

Cited By ~ 2

Author(s):

Paul Gressenberger

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Invasive Procedure ◽

Bleeding Risk ◽

Study Data ◽

Current Evidence ◽

Bleeding Complications ◽

Bleeding Events ◽

Reversal Agent

Summary. Administration of direct oral anticoagulants (DOACs) for the treatment of venous thrombotic events (VTE) or non-valvular atrial fibrillation (AF) is now standard of care and has demonstrated clinical efficacy and safety in numerous clinical studies. Usually these substances have lower overall mortality and less risk of cerebral hemorrhage, but depending on the substance and study, they are more likely to cause gastrointestinal bleeding than vitamin K antagonists (VKA), the medication that used to be standard for VTE and AF. Since DOACs have very short plasma elimination half-lives compared to VKA, for most bleeding events, expert opinions suggest that withdrawal of DOACs and supportive care will likely suffice to stop a bleeding episode. Because there is a bleeding risk associated with DOACs, reversal strategies may be needed if a patient receiving DOAC therapy bleeds during surgery or an invasive procedure. So far, idarucizumab has been the only available antidote that binds specifically to dabigatran and safely and quickly reverses its anticoagulant effects. Idarucizumab has no effects on anti Xa inhibitors or other anticoagulants. To date, treatment of serious, life-threatening bleeds in patients with anti-Xa-inhibitor has involved 4 factor prothrombin complex concentrates (PCC). PCC restores normal hemostasis laboratory values in most patients with major bleeding events after anti Xa inhibitor intake. Recently, the US Food and Drug Administration (FDA) approved andexanet alfa as the first specific antidote for the anti-Xa inhibitors apixaban and rivaroxaban. So far clinical experience with this substance and data comparing it with PCC are lacking. Currently ciraparantag is under investigation as a universal reversal agent for all DOACs and low molecular weight heparin as well. Because it is so broadly applicable, ciraparantag might be a good future option for the management of most bleeding complications under anticoagulant treatment. The aim of this review is to summarize recent study data and recommendations on nonspecific and specific DOAC reversal strategies and to present the current evidence.

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Direct Oral Anticoagulant Plasma Levels for the Management of Acute Ischemic Stroke

Cerebrovascular Diseases ◽

10.1159/000502335 ◽

2019 ◽

Vol 48 (1-2) ◽

pp. 17-25 ◽

Cited By ~ 3

Author(s):

Armin Marsch ◽

Kosmas Macha ◽

Gabriela Siedler ◽

Lorenz Breuer ◽

Erwin F. Strasser ◽

...

Keyword(s):

Ischemic Stroke ◽

Plasma Level ◽

Acute Ischemic Stroke ◽

Plasma Levels ◽

Emergency Treatment ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Complications ◽

Vessel Occlusion

Introduction: The management of acute ischemic stroke in patients on direct oral anticoagulants (DOACs) is challenging. However, the substance-specific plasma level could guide treatment decisions on recanalization therapies. We present a plasma-level-based protocol for emergency treatment of stroke patients on oral anticoagulants. Bleeding complications and clinical outcome for patients on DOACs are reported and compared to patients on vitamin K antagonists (VKAs). Methods: In patients with acute ischemic stroke and suspected use of DOACs within 48 h prior to hospital admission, plasma levels were measured using the calibrated Xa-activity (apixaban, edoxaban, rivaroxaban) or the Hemoclot®-assay (dabigatran). Levels <50 ng/mL were supportive for thrombolysis, while high values >100 ng/mL excluded patients from recombinant tissue plasminogen activator use. For patients on VKAs, the cutoff was set at international normalized ratio of 1.7. Endovascular thrombectomy of a large vessel occlusion was performed independently from coagulation testing. Consecutive patients were included in an observational registry. Results: Five hundred and twenty-two patients (261 on VKAs and 261 on DOACs) were included. Thirty patients (11.5%) on VKAs and 24 (9.2%) on DOACs received thrombolysis, followed by mechanical thrombectomy in 10 and 14 patients, respectively. Seventeen patients in each group received thrombectomy only. Symptomatic intracranial hemorrhage associated with thrombolysis occurred in 1 patient on VKA (3.3%) and 1 on DOAC (4.2%; p = 0.872). The turnaround time of specific assays did not show a significant delay in comparison to standard coagulation parameters. Conclusion: DOAC plasma levels could support decisions on emergency treatment of ischemic stroke. Systemic thrombolysis below suggested thresholds appears preliminary feasible and safe without an excess in bleeding complications.

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New direct oral anticoagulants – current therapeutic options and treatment recommendations for bleeding complications

Thrombosis and Haemostasis ◽

10.1160/th12-05-0319 ◽

2012 ◽

Vol 108 (10) ◽

pp. 625-632 ◽

Cited By ~ 53

Author(s):

Erhard Seifried ◽

Wolfgang Miesbach

Keyword(s):

Emergency Management ◽

Elective Surgery ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Vii ◽

Bleeding Complications ◽

Management Options ◽

Spontaneous Bleeding ◽

Long Term Treatment

SummaryTo date, clinical studies show that the incidence of spontaneous bleeding with new direct oral anticoagulants (DOAs) is comparable to that of established anticoagulants. However, unlike vitamin K antagonists, there are currently no clinically available antidotes or approved reversal agents for new DOAs. Restoring normal coagulation is important in many cases, such as emergency surgeries, serious bleedings, or anticoagulant overdosing. Attempts have been made to restore normal coagulation after treatment with new DOAs using compounds such as recombinant activated factor VII (rFVIIa), prothrombin complex concentrate (PCC), or FEIBA (factor eight inhibitor bypassing activity). Limited pre-clinical data and even less clinical evidence are available on the usefulness of these methods in restoring normal coagulation for the emergency management of critical bleeding episodes. Evaluating the utility of DOAs is further complicated by the fact that it is unknown how predictive established test systems are of the bleeding risks. Clinical practice requires further evaluation of the emergency management options for the new DOAs to define the agents and the doses that are most useful. Furthermore, patients receiving long-term treatment with a DOA are likely to undergo elective surgery at some point, and there is lack of evidence regarding perioperative treatment regimens under such conditions. This review summarises potential bleeding management options and available data on the new DOAs.

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Heparins – DOACS – VKA

Phlebologie ◽

10.12687/phleb2289-6-2015 ◽

2015 ◽

Vol 44 (06) ◽

pp. 307-315 ◽

Cited By ~ 2

Author(s):

H. Schinzel

Keyword(s):

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Prolonged Treatment ◽

Bleeding Complications ◽

Individual Risk ◽

Additional Risk Factor ◽

Vte Prophylaxis ◽

Patients With Cancer ◽

Increased Risk

SummaryPatients with cancer are at increased risk of venous thromboembolism (VTE). At the same time they have often an underlying bleeding risk. That can often make decisions surrounding the administration of anticoagulants complicate. Individual risk-benefit calculation is necessary. During hospital stage the patients get, if there are no contraindications, a medical VTE prophylaxis with low molecular weight heparin (LMWH). Whereas out-patients don’t get a prophylaxis because they are at low risk of thromboembolism. If additional risk factor for VTE exists a decision for medical VTE prophylaxis should be taken into account. In patients with cancer and acute VTE, LMWH is recommended as treatment of choice for initial and long-term management in a body weight adapted dosage. After a period of 3–6 month and if a prolonged treatment is necessary, guidelines allow to switch from LMWH to VKA for further anticoagulant therapy. Beside the established anticoagulants like heparin, vitamin K antagonists, fondaparinux new oral direct anticoagulants (DOACs) were established in the last years. These substances are evaluated in in clinical trials. They are approved for treatment of acute VTE, for secondary prophylaxis and for prevention of ischemic stroke in patients with arterial fibrillation. In the VTE trials, 4–10 % of the enrolled patients had a history of cancer. The data shows that DOACs can prevent recurrent VTE as good as standard therapy with enoxaparin/warfarin without more bleeding complications. The results are encouraging. Because of the limited data the direct oral anticoagulants are not recommended for treatment of VTE at this time. Further studies are necessary.

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