Update on Direct Oral AntiCoagulants (DOACs)

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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Update on Direct Oral AntiCoagulants (DOACs)

Hämostaseologie ◽

10.5482/hamo-16-10-0041 ◽

2017 ◽

Vol 37 (04) ◽

pp. 267-275 ◽

Cited By ~ 3

Author(s):

Christoph Rosenthal ◽

Christian von Heymann ◽

Jürgen 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.

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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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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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Primary Thromboprophylaxis in Patients with Malignancies: Daily Practice Recommendations by the Hemostasis Working Party of the German Society of Hematology and Medical Oncology (DGHO), the Society of Thrombosis and Hemostasis Research (GTH), and the Austrian Society of Hematology and Oncology (ÖGHO)

Cancers ◽

10.3390/cancers13122905 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2905

Author(s):

Martin Kirschner ◽

Nicole do Ó Hartmann ◽

Stefani Parmentier ◽

Christina Hart ◽

Larissa Henze ◽

...

Keyword(s):

Risk Factors ◽

Cancer Patients ◽

Vitamin K Antagonists ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Working Party ◽

Major Surgery ◽

Thrombotic Risk ◽

Indwelling Catheters ◽

Increased Risk

Patients with cancer, both hematologic and solid malignancies, are at increased risk for thrombosis and thromboembolism. In addition to general risk factors such as immobility and major surgery, shared by non-cancer patients, cancer patients are exposed to specific thrombotic risk factors. These include, among other factors, cancer-induced hypercoagulation, and chemotherapy-mediated endothelial dysfunction as well as tumor-cell-derived microparticles. After an episode of thrombosis in a cancer patient, secondary thromboprophylaxis to prevent recurrent thromboembolism has long been established and is typically continued as long as the cancer is active or actively treated. On the other hand, primary prophylaxis, even though firmly established in hospitalized cancer patients, has only recently been studied in ambulatory patients. This recent change is mostly due to the emergence of direct oral anticoagulants (DOACs). DOACs have a shorter half-life than vitamin K antagonists (VKA), and they overcome the need for parenteral application, the latter of which is associated with low-molecular-weight heparins (LMWH) and can be difficult for the patient to endure in the long term. Here, first, we discuss the clinical trials of primary thromboprophylaxis in the population of cancer patients in general, including the use of VKA, LMWH, and DOACs, and the potential drug interactions with pre-existing medications that need to be taken into account. Second, we focus on special situations in cancer patients where primary prophylactic anticoagulation should be considered, including myeloma, major surgery, indwelling catheters, or immobilization, concomitant diseases such as renal insufficiency, liver disease, or thrombophilia, as well as situations with a high bleeding risk, particularly thrombocytopenia, and specific drugs that may require primary thromboprophylaxis. We provide a novel algorithm intended to aid specialists but also family practitioners and nurses who care for cancer patients in the decision process of primary thromboprophylaxis in the individual patient.

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

Thrombosis Research ◽

10.1016/j.thromres.2020.07.054 ◽

2020 ◽

Vol 195 ◽

pp. 243-249

Author(s):

Ji Yun Lee ◽

Il-Young Oh ◽

Ju-Hyeon Lee ◽

Sang-Young Kim ◽

Seong Soon Kwon ◽

...

Keyword(s):

Drug Interactions ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Risk Of Bleeding ◽

Increased Risk

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Recent advances in the treatment and prevention of venous thromboembolism in cancer patients: role of the direct oral anticoagulants and their unique challenges

F1000Research ◽

10.12688/f1000research.18673.1 ◽

2019 ◽

Vol 8 ◽

pp. 974 ◽

Cited By ~ 3

Author(s):

Dominique Farge ◽

Corinne Frere

Keyword(s):

Venous Thromboembolism ◽

Cancer Patients ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Patient Characteristics ◽

Primary Prophylaxis ◽

Disease Stage ◽

Vte Prophylaxis ◽

Patients With Cancer ◽

Increased Risk

Venous thromboembolism (VTE) is a common complication in patients with cancer and is associated with poor prognosis. Low-molecular-weight heparins (LMWHs) are the standard of care for the treatment of cancer-associated thrombosis. Primary VTE prophylaxis with LMWH is recommended after cancer surgery and in hospitalized patients with reduced mobility. However, owing to wide variations in VTE and bleeding risk, based on disease stage, anti-cancer treatments, and individual patient characteristics, routine primary prophylaxis is not recommended in ambulatory cancer patients undergoing chemotherapy. Efforts are under way to validate risk assessment models that will help identify those patients in whom the benefits of primary prophylaxis will outweigh the risks. In recent months, long-awaited dedicated clinical trials assessing the direct oral anticoagulants (DOACs) in patients with cancer have reported promising results. In comparison with the LMWHs, the DOACs were reported to be non-inferior to prevent VTE recurrence. However, there was an increased risk of bleeding, particularly in gastrointestinal cancers. Safe and optimal treatment with the DOACs in the patient with cancer will require vigilant patient selection based on patient characteristics, co-morbidities, and the potential for drug–drug interactions.

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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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Potential Drug Interactions Between Cannabinoids and Its Derivatives and Oral Anticoagulants

Hospital Pharmacy ◽

10.1177/0018578720985438 ◽

2021 ◽

pp. 001857872098543

Author(s):

McKenzie Paduch ◽

Angela R. Thomason

Keyword(s):

Drug Interactions ◽

English Language ◽

Case Reports ◽

Oral Anticoagulants ◽

Direct Oral Anticoagulants ◽

Thromboembolic Events ◽

Potential Drug ◽

Risk Of Bleeding ◽

Increased Risk ◽

Potential Risks

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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