The increased risk of bleeding due to drug-drug interactions in patients administered direct oral anticoagulants

The increase use of cannabidiol containing products poses potential risks with high-alert medications such as oral anticoagulants. To review the use of cannabidiol and its’ derivatives with oral anticoagulants, searches (2005-May 2020) were performed by PubMed, Google Scholar, and ClinicalTrials.gov. Articles were limited to English-language only. The results yielded 4 case reports evaluating the potential drug interactions between cannabinoids and its’ derivatives and oral anticoagulants. These case reports show the potential for drug interactions when using warfarin and cannabidiol containing products. At time of publication, there were no published articles on drug interactions between cannabidiol and the direct oral anticoagulants. Further research is needed to conclude drug interactions are associated with an increased risk of bleeding or thromboembolic events in these patients.

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Anticoagulation Regimens and Interventional Pain Procedures

10.1093/med/9780190271787.003.0039 ◽

2018 ◽

Author(s):

Christine Oryhan ◽

Kevin Vorenkamp ◽

Daniel Warren

Keyword(s):

Chronic Pain ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Patient Characteristics ◽

The United States ◽

Bleeding Complications ◽

Risk Of Bleeding ◽

Increased Risk ◽

Spinal Epidural ◽

The Ideal

With the aging population and new anticoagulant medications, such as direct oral anticoagulants, being marketed in the United States, it is very important for pain physicians to be aware of the anticoagulants available and how they affect the safety of interventional pain procedures. In addition to anticoagulant and antiplatelet medications, other medications commonly used in the chronic pain population may put patients at increased risk of bleeding complications. Certain patient characteristics, particularly in the chronic pain population, may also increase a patient’s risk of bleeding. The chapter reviews common and emerging anticoagulant and antiplatelet medications and the ideal holding time before or after interventional pain procedures, particularly in the spine. The chapter also discusses the diagnosis, treatment, and outcomes of spinal epidural hematomas.

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Comparative effectiveness and safety of low-strength and high-strength direct oral anticoagulants compared with warfarin: a sequential cohort study

BMJ Open ◽

10.1136/bmjopen-2018-026486 ◽

2019 ◽

Vol 9 (5) ◽

pp. e026486 ◽

Cited By ~ 4

Author(s):

Nicole L Pratt ◽

Emmae Ramsay ◽

Lisa M Kalisch Ellett ◽

Katherine Duszynski ◽

Sepehr Shakib ◽

...

Keyword(s):

Myocardial Infarction ◽

Cohort Study ◽

Propensity Score ◽

Ischaemic Stroke ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

High Strength ◽

Risk Of Bleeding ◽

Increased Risk ◽

Low Strength

ObjectivesThe aim of this study was to compare effectiveness and safety of low-strength and high-strength direct oral anticoagulants (DOACs) with warfarin in the Australian Veteran population.DesignSequential cohort study using inverse probability of treatment weighting (IPTW) and propensity score matching. Initiators of high-strength (apixaban 5 mg, dabigatran 150 mg, rivaroxaban 20 mg) and low-strength DOACS (apixaban 2.5 mg, dabigatran 110 mg, rivaroxaban 15 mg) were compared with warfarin initiators.SettingAustralian Government Department of Veterans’ Affairs claims database.Participants4836 patients who initiated oral anticoagulants (45.8%, 26.0% and 28.2% on low-strength, high-strength DOACs and warfarin, respectively) between August 2013 and March 2015. Mean age was 85, 75 and 83 years for low-strength, high-strength DOACs and warfarin initiators, respectively.Main outcome measuresOne-year risk of hospitalisation for ischaemic stroke, any bleeding event or haemorrhagic stroke. Secondary outcomes were 1-year risk of hospitalisation for myocardial infarction and death.ResultsUsing the IPTW method, no difference in risk of ischaemic stroke or bleeding was found with low-strength DOACs compared with warfarin. As a class, no increased risk of myocardial infarction was found for low-strength DOACs, however, risk was elevated for apixaban (HR 2.25, 95% CI 1.23 to 4.13). For high-strength DOACs, no difference was found for ischaemic stroke compared with warfarin, however, there was a significant reduction in risk of bleeding events (HR 0.63, 95% CI 0.44 to 0.89) and death (HR 0.40, 95% CI 0.28 to 0.58). Propensity score matching showed no difference in risk of ischaemic stroke or bleeding.ConclusionWe found that in the practice setting both DOAC formulations were similar to warfarin with regard to effectiveness and had no increased risk of bleeding.

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Update on Direct Oral AntiCoagulants (DOACs)

Phlebologie ◽

10.1055/s-0038-1657856 ◽

2018 ◽

Vol 47 (03) ◽

pp. 137-145

Author(s):

C. Rosenthal ◽

C. von Heymann ◽

J. Koscielny

Keyword(s):

Elective Surgery ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Patient Characteristics ◽

Clinical Decision ◽

Major Surgery ◽

Preoperative Treatment ◽

Risk Of Bleeding ◽

Increased Risk ◽

Meta Analyses

SummaryRecent findings require an update of previous recommendations for the perioperative use of Direct Oral AntiCoagulants (DOACs). A break in preoperative treatment of 24-96 hours is recommended based on the pharmacokinetic profiles of DOACs and depends on individual patient characteristics, their renal and possibly liver function, and their surgery-related risk of bleeding. In cases of renal or hepatic insufficiency, whether to extend the preoperative interruption of IIa- and Xa-inhibitors is a clinical decision that must be reached on an individual patient basis. In cases of epidural or spinal anaesthesia, more conservative pausing-intervals are recommended due to the risk of persistent neurologic deficits (e.g., paraplegia) following the development of spinal subdural and epidural haematomas. Elective surgery should be postponed according to these recommendations. Preoperative “bridging” with LMWH (more precisely referred to as “switching”) should be omitted due to a significantly increased risk of bleeding. In addition, the incidence of perioperative thromboembolic risks, such as DVT, PE, and stroke, are no different whether interruption or „switching” is undertaken. Postoperatively, the DOACs can be reinstituted within the first 24 hours. In cases of major surgery or if there is a higher risk of bleeding, resumption of DOACS should only begin after 24-72 hours. In patients with an elevated thromboembolic risk, transient postoperative LMWH administration can be recommended during this period.Interaction of DOACs with other drugs usually occurs during the absorption, transport and elimination of these drugs. Therefore, substance-specific restrictions and recommendations should be observed during these times. In everyday clinical practice, webbased, independent information portals on drug-interactions are very helpful in providing safe and rapid information about potential interactions when DOACs are used in combination with other drugs, especially during perioperative management.Non-adherence to medications is a worldwide problem that has dangerous and costly consequences. Present data suggest that persistence is the primary factor that supports adherence. Despite the adherence data presented in the DOACS approval studies (e.g., persistence in the treatment of acute venous thromboembolism has been reported to be between 94-99%), the first registries and meta-analyses provide sobering results regarding the incidence of persistence and the success rate of interventions designed to improve adherence with DOACs in cases of long-term usage.Nachdruck aus und zu zitieren als: Hämostaseologie 2017; 37: 267–275 https://doi.org/10.5482/HAMO-16-10-1657856

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Slightly elevated international normalized ratio predicts bleeding episodes in patients treated with direct oral anticoagulants

Journal of International Medical Research ◽

10.1177/0300060519894439 ◽

2020 ◽

Vol 48 (6) ◽

pp. 030006051989443

Author(s):

Priya Bhardwaj ◽

Louise Breum Petersen ◽

Tomas Sorm Binko ◽

Jan Roland Petersen ◽

Gitte Gleerup Fornitz

Keyword(s):

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Factor Xa ◽

Bleeding Risk ◽

International Normalized Ratio ◽

Direct Factor ◽

Risk Of Bleeding ◽

Increased Risk ◽

Direct Factor Xa Inhibitors ◽

Bleeding Episodes

Introduction Patients treated with direct oral anticoagulants (DOACs) are at increased bleeding risk. It is therefore of increasing interest to identify predictors of bleeding episodes to increase safety during treatment with DOACs. Methods This retrospective cohort study systematically reviewed medical records of 235 patients treated with either apixaban, rivaroxaban or dabigatran for non-valvular atrial fibrillation or venous thromboembolism and collected data on the international normalized ratio (INR) and all bleeding episodes. Results INR ≥ 1.5 was significantly associated with increased risk of minor and major bleeding events in patients treated with direct factor Xa inhibitors. This association was not present in patients treated with dabigatran. However, a high negative predictive value was identified for INR < 1.5 for all drugs. The relative risks of bleeding episodes in patients with INR ≥ 1.5 and INR < 1.5 were 5.1 and 0.20, respectively. Conclusions Our results demonstrate a strong correlation between INR and risk of bleeding episodes during DOAC treatment. INR < 1.5 was a strong negative predictor for low bleeding risk independent of indication or choice of drug, and INR ≥ 1.5 was associated with increased risk of bleeding episodes in patients treated with direct factor Xa-inhibitors.

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Abstract 15740: Concomitant Use of Dronedarone and Direct Oral Anticoagulants and Risk of Bleeding in Patients With Atrial Fibrillation: An Analysis of the U.S. Truven Health MarketScan Database

Circulation ◽

10.1161/circ.142.suppl_3.15740 ◽

2020 ◽

Vol 142 (Suppl_3) ◽

Author(s):

Sampada K Gandhi ◽

Michael D Ezekowitz ◽

James A Reiffel ◽

Rania Boiron ◽

Mattias Wieloch

Keyword(s):

Atrial Fibrillation ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Incidence Rates ◽

Cox Proportional Hazards ◽

Concomitant Treatment ◽

Gi Bleeding ◽

Risk Of Bleeding ◽

Combined Use ◽

Increased Risk

Introduction: Dronedarone (DR), a P-gp and CYP 3A4 inhibitor may increase exposure and the risk of bleeding when combined with direct oral anticoagulants (DOACs). Objective: To examine the association between concomitant use of DR and the DOACs, apixaban (A), dabigatran (D), and rivaroxaban (R), and risk of bleeding compared to DOAC monotherapy in patients with atrial fibrillation (AF). Methods: A retrospective cohort study using a U.S. claims database, Truven Health MarketScan identified new users of A, D, and R in patients with AF ≥18 years from Jan 1, 2007 to Sep 30, 2017. Bleeding was defined as hospitalization or emergency room visit with a primary diagnosis of gastrointestinal (GI) bleeding, intracranial hemorrhage (ICH), or bleeding at other sites. Risk of overall and by type of bleeding was examined in concomitant users of DOAC and DR compared to patients using DOAC alone after adjusting for covariates of interest and applying propensity score (PS) trimming via Cox proportional hazards modeling. Results: Among concomitant users of DR and A (1,932), D (3,117), and R (2,395), crude incidence rates of bleeding per 1,000 person-years were 17.2, 37.8, 61.8, respectively versus 26.8, 31.3, and 44.9 in users of A (51,420), D (42,312), and R (57,300) alone. Incidence rates stratified by PS showed higher bleeding incidence in concomitant users of DR with D or R, but not with A. No increased bleeding risk was associated with use of DR and A vs A alone [Adjusted Hazard ratio (aHR): 0.69 (95% CI: 0.40, 1.17), p=0.16]. A modestly increased risk of GI bleeding but not overall bleeding was associated with combined use of DR and D vs D alone [aHR bleeding: 1.18 (95% CI: 0.89, 1.56), p=0.26; aHR GI bleeding: 1.40 (95% CI: 1.01, 1.93); p=0.04]. An increased risk of overall bleeding, driven by GI bleeding, was associated with combined use of DR and R vs R alone [aHR bleeding:1.31 (95% CI: 1.01, 1.69); p=0.04; aHR GI bleeding:1.39 (95% CI: 0.98, 1.95); p=0.06]. There was no increase in the risk of ICH associated with combined use of DR and any DOAC. Conclusions: Concomitant treatment with DR and A showed no increased risk of bleeding, but DR increased the risk of GI bleeding when given with D or R, and of overall bleeding only with R. Concomitant treatment with DR and any DOAC did not increase ICH risk.

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The Impact of Body Weight and Renal Function on the Risk of Bleeding With Direct Oral Anticoagulants in Atrial Fibrillation

Annals of Pharmacotherapy ◽

10.1177/1060028021995201 ◽

2021 ◽

pp. 106002802199520

Author(s):

Hannah Whittemore ◽

Andrew K. Posen ◽

Erika L. Hellenbart ◽

Vicki Groo ◽

Eric Wenzler ◽

...

Keyword(s):

Atrial Fibrillation ◽

Renal Function ◽

Body Weight ◽

Renal Dysfunction ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk ◽

The Impact

Background: Atrial fibrillation (AF) increases the risk of stroke and direct oral anticoagulants (DOACs) are first-line agents for prevention. Gaps in the literature cause reluctance in prescribing DOACs for patients with renal dysfunction and/or extremes in body weight. Objective: To evaluate the impact body weight and renal function have on major and clinically relevant nonmajor (CRNM) bleeding events and ischemic strokes in AF patients receiving a DOAC. Methods: This retrospective cohort study included adults with nonvalvular atrial fibrillation (NVAF) or atrial flutter (AFL) receiving a DOAC ≥12 months. The primary outcome was a composite of major and CRNM bleeding events. Secondary outcomes included ischemic stroke and risk factors for bleeding events. Results: Of the 233 patients analyzed, 25 patients experienced a bleeding event. Patients who bled weighed 10 kg less ( P = 0.043) than those who did not and had a higher HASBLED score ( P = 0.003). Multivariate logistic regression identified weight ( P = 0.048), serum creatinine (SCr; P = 0.027), and HASBLED score ( P = 0.024) as the significant predictors for experiencing a bleed. Three patients experienced a stroke. Conclusion and Relevance: This study demonstrates an association between higher baseline SCr, elevated HASBLED score, and lower weight, with an increased risk of bleeding in patients with NVAF or AFL receiving a DOAC. These findings add to prescribing considerations when initiating DOACs. Closer monitoring is advised for patients with significant renal dysfunction and/or low body weight, even with renal dose adjustments.

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Are Direct Oral Anticoagulants Plasma Concentrations Associated with the Risk of Postoperative Bleeding? Results from the Real Life Cohort

Blood ◽

10.1182/blood.v128.22.3819.3819 ◽

2016 ◽

Vol 128 (22) ◽

pp. 3819-3819

Author(s):

Pável Olivera ◽

Vicente Cortina ◽

Verónica Pons ◽

Tania Canals ◽

Erik Johansson ◽

...

Keyword(s):

High Risk ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Postoperative Bleeding ◽

Plasma Concentrations ◽

Thrombin Inhibitor ◽

Bleeding Events ◽

Risk Of Bleeding ◽

Increased Risk

Abstract Background The perioperative management (PM) of direct oral anticoagulants (DOACs) is controversial. The role of assessing DOAC plasma levels in order to ensure a safe use of these anticoagulants is still unknown. Aims To examine the association between DOACs plasma concentrations obtained before surgery and the risk of postoperative bleeding in the perioperative setting. Methods From June 2014 to December 2015 we have consecutively included 99 patients treated with DOACs and referred to our Unit for PM. Management was performed following the PM recommendations from the Catalan Thrombosis Working Group (Tromboc@t) . Bleeding events were classified following the ISTH criteria. Plasma concentrations were measured in the day of invasive procedure using the Technoclone anti-Xa assay from Technoclone (Vienna-Austria) for Rivaroxaban and Apixaban, and the Direct Thrombin Inhibitor Assay from IL (Bedford-MA-USA) for Dabigatran; in each case, specific calibrators were used. Patients were systematically followed 30 days after the surgical procedure. Results A total of 99 patients were recruited. Median age was 76 years (range: 61-94) and 51 (51.5%) were female. Among them, 23 patients received dabigatran, 40 rivaroxaban and 36 apixaban. As per the risk scores, 66.7% of the patients had a CHA2DS2-VASc score >3, 57.6% had a HAS-BLED score >3, and 51 (51.5%) were considered high-risk procedures. Total bleeding events occurred in 23 patients (47.8% minor, 30.4% non-major clinically relevant, and 21.7% major bleeding). The median plasma NOACs concentration was 38.3 ng/ml (0.8-226 ng/ml), with 32 patients having levels >30 ng/mL. HASBLED score > 3 was associated with an increased risk of bleeding events within 30 days (hazard ratio (HR)= 3.9, 95% CI= 1.14-13.4, P=0.03). Plasma DOAC levels > 30 ng/ml were not significantly associated with an increased risk of bleeding events (HR=2.17, 95% CI=0.862-6.67, P=0.10). Major bleeding (n=5) was probably associated with the risk of the procedure than to the DOAC plasma concentrations. Conclusion In our cohort we found significant association between the individual bleeding risk before surgery with the risk of postoperative bleeding. In spite of that, this study will continue to reevaluate PM in high-risk procedures according to plasma DOAC levels. Disclosures No relevant conflicts of interest to declare.

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Anticoagulation in Peripheral Artery Disease: Are We There Yet?

Vascular and Endovascular Review ◽

10.15420/ver.2019.10 ◽

2020 ◽

Vol 3 ◽

Author(s):

Alessandro Cannavale ◽

Mariangela Santoni ◽

Giuseppe Cannavale ◽

Fabrizio Fanelli

Keyword(s):

Peripheral Artery Disease ◽

Controlled Trial ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Peripheral Artery ◽

Unfractioned Heparin ◽

Risk Of Bleeding ◽

Increased Risk ◽

Artery Disease ◽

Randomised Controlled

Thromboembolism in patients with peripheral artery disease (PAD) represents a common cause of morbidity and mortality. In this article, the authors analyse the use of anticoagulants for patients with PAD. Anticoagulants have been used to reduce the risk of venous thromboembolism, but have recently been applied to the arterial circulation. Heparins were introduced to reduce short-term major adverse limb events in patients undergoing arterial revascularisation. Low molecular weight heparins have allowed easier management and carry a lower risk of bleeding than unfractioned heparin. Vitamin K anticoagulants have been tested in trials that included patients with PAD, showing an increased risk of bleeding when compared with aspirin alone, but longer patency rates for venous surgical bypass, although the evidence remains weak. Those anticoagulants are currently recommended only in patients with PAD who need anticoagulation for other diseases. Direct oral anticoagulants have only recently been investigated for use in patients with PAD. Promising results from low dose rivaroxaban plus aspirin have been recently outlined by a randomised controlled trial and supported by international guidelines.

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Drug-drug interactions in atrial fibrillation patients receiving direct oral anticoagulants

Scientific Reports ◽

10.1038/s41598-021-01786-2 ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Ji Yun Lee ◽

Il-Young Oh ◽

Ju-Hyeon Lee ◽

Seok Kim ◽

Jihoon Cho ◽

...

Keyword(s):

Atrial Fibrillation ◽

Ischemic Stroke ◽

Drug Interactions ◽

Major Bleeding ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Multiple Logistic Regression Analysis ◽

Common Data Model ◽

Concomitant Treatment ◽

Increased Risk

AbstractPolypharmacy is common in patients with atrial fibrillation (AF), making these patients vulnerable to the occurrence of potential drug-drug interactions (DDIs). We assessed the risk of ischemic stroke and major bleeding in the context of concomitant treatment with potential DDIs in patients with AF prescribed direct oral anticoagulants (DOACs). Using the common data model (CDM) based on an electronic health record (EHR) database, we included new users of DOACs from among patients treated for AF between January 2014 and December 2017 (n = 1938). The median age was 72 years, and 61.8% of the patients were males, with 28.2% of the patients having a CHA2DS2-VASc score in category 0–1, 49.4% in category 2–3, and 22.4% in category ≥ 4. The CHA2DS2-VASc score was significantly associated with ischemic stroke occurrence and hospitalization for major bleeding. Multiple logistic regression analysis showed that increased risk of ischemic stroke and hospitalization for major bleeding was associated with the number of DDIs regardless of comorbidities: ≥ 2 DDIs was associated with ischemic stroke (OR = 18.68; 95% CI, 6.22–55.27, P < 0.001) and hospitalization for major bleeding (OR = 5.01; 95% CI, 1.11–16.62, P < 0.001). DDIs can cause reduced antithrombotic efficacy or increased risk of bleeding in AF patients prescribed DOACs.

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