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Venous Thromboembolic (VTE) prophylaxis: Part III: general considerations in reducing and preparing for unexpected bleeding events with the NOACs.

Recap of Parts I & II

Parts I and II of this series on VTE prophylaxis (Goldstein, 2014, 2015) have focused on reviews of new medications available for prevention of coagulopathies following orthopedic surgeries and diagnoses of non-valvular atrial fibrillation, drug interactions leading to increased bleeding risks with these medications, and new antidotes under study to treat acute bleeding events for patients taking the new anticoagulant medications. This final installment of the three-part update will address easily used screening checklists for nurses to use at the bedside that assess bleeding risk and stroke risk for patients, as well as emergency responses for patients who are observed to have uncontrolled, acute bleeding events while taking any of the anticoagulant medications we have reviewed.

Assessing Patients at Risk

In some cases, as rare as they may be, patients may be admitted to a med-surg floor with an unreported history of atrial fibrillation (afib) or prior warfarin use.A simple and easily completed bedside checklist for stroke risk among those with afib is the CHADS-2, a scale originally developed in 2001 in order to assign risk scores for stroke based upon clinical history and risk factors present (Gage et al., 2001; Levine, 2014).

Readers may see reference to a newer, updated CHADS scale (the CHA2DS2-VASc system), developed by the European Society of Cardiology (ESC), which adds three additional measures for predicting stroke risk and appears to add greater sensitivity in predicting strokes (Lip, Nieuwlaat, Pisters, Lane, & Crijns, 2010). An online version of the CHA2DS2 score calculator (widely accepted in Europe and the United Kingdom) is available at http://www.qxmd. com/calculate-online/cardiology/chads2-stroke-risk-in-atrialfibrillation to assist in determining percentage of stroke risk.

However, in the United States, the 2012 update of practice recommendations by the American College of Chest Physicians (Guyatt et al., 2012) recommends the original CHADS-2 scoring system for assessment and treatment of patients at risk. On the CHADS-2, anyone scoring 2 or more is considered high risk for stroke within the next year.

Clinicians may also wish to familiarize themselves with bleeding risk assessment tools in the medical literature. One --helpful and simple assessment tool is the HAS-BLED assessment, which yields a I-year bleeding risk score based upon clinical history (Pisters et al., 2010). Anyone who scores a total of 3 or greater on the HAS-BLED Scale is at high risk for a bleeding event over the next year (Coagulation Center, 2015).An online HAS-BLED score calculator can be found at and may be used to evaluate bleeding risk percentage.

If physicians are not aware of a risk assessment of 3 or more on a given patient, they need to be informed and nurses should be cautious in the use of any NSAIDs with such patients, even if NSAIDS have been approved on the patient electronic MAR. It is the experience of this writer that such medication interactions are often missed or overlooked during pharmacy reconciliations.

Treating Unexpected Bleeding Events

Some facilities have developed emergency protocols for acute or life- or limb-threatening bleeding events for patients taking any Factor IIa or Factor Xa oral anticoagulant, which involves the following step-wise treatment approach (Kumar, Smith, & Henry, 2015; Vilchez, Gallego, & Lip, 2014).

Step I: Withhold anticoagulant; start timed monitoring of PT, aPTT, and TT (Thrombin Time).

Step 2: Transfuse blood products high in plasma.

Step 3: Consider need for surgery or embolization.

Step 4: Activate charcoal to reduce additional absorption if dabigatran or rivaroxaban taken within 2 hours or apixaban within 3 hours.

Step 5: Consider hemodialysis with dabigatran only.

Step 6: Consider antifibrinolytic therapy.

Step 7: Consider PCCs (rivaroxaban/apixaban) (Perlstein et al., 2014).

Nursing staff also need to be aware of drug-drug interactions with the NOACs. By examining Table 5, readers will notice that all of the NOACs, excluding warfarin, are substrates for the P-glycoprotein (P-gp) transport system. This makes all of these drugs susceptible to influences of P-gp inhibitors. These inhibitors will decrease elimination of the medication, prolonging half-lives and increasing plasma concentrations. Specific P-gp inhibitors nurses need to be wary of (especially with impaired renal function) include: ketoconazole, dronedarone, amiodarone, verapamil, dilitiazem, clarithromycin.

Hepatic metabolism occurs primarily via the cytochrome P-450 system (CYP) and includes both the 3A4 and 2)2 families of enzymes. Due to the involvement of CYP3A4 in all of the NOACs except dabigatran, plasma concentrations of apixaban, edoxaban, and rivaroxaban can become elevated in the presence of strong inhibitors.These strong inhibitors include: ketoconazole, itraconazole, conivaptan,HIV protease inhibitors, and clarithromycin.There are other weaker inhibitors and inducers that were also examined by Mohrien, Oliphant, and Self (2013) in an excellent review of these important drug interactions.

Increased bleeding risks due to aspirin and NSAID use were reviewed in Part I of this series (Goldstein, 2014).


The use of Factor lla and Factor Xa oral anticoagulants will likely increase and continue over the next several years. Nurses need to be aware of drug interactions that directly affect the bleeding risks of their patients. In addition, nurses also need to prepare for possible adverse bleeding events associated with these medications. Identifying unexpected bleeding in any patient prescribed these medications is the first step in reversing the event. Being aware of research on specific antidotes and specific procedures, such as the use of hemodialysis and PCCs, can help save lives. Unfortunately, there are no FDA approved or licensed antidotes for the Factor IIa or Factor Xa oral anticoagulants at this time. Questioning dosing and use of these medications in patients with moderate to severe renal or hepatic impairment is also an important nursing intervention to prevent adverse drug events associated with all anticoagulant medications.

Note: Tables 1 and 2 can be found with Part I of this series, which appeared on pages 14-15 of the September/October 2014 issue of MedSurg Matters! Tables 3 and 4 can be found with Part II, which appeared on pages 9-13 of the July/August 2015 issue.


Coagulation Center. (2015). HAS-BLED risk assessment pocket guide. Retrieved June 1, 2015, from assets/pdf/HAS-BLED_Pocket_Guide.pdf

Dager, W.E. (201 I). Using prothrombin complex concentrates to rapidly reverse oral anticoagulant effects. The Annals of Pharmacotherapy, 45(7-8), 1016-1020.

Gage, B.F., Waterman, A.D., Shannon, W" Boechler, M., Rich, M.W., & Radford M.J. (2001). Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. Journal of the American Medical Association, 285(22), 28642870.

Goldstein, P.C. (2014). Venous thromboembolic (VTE) prophylaxis: Part I--NSAIDs found to significantly increase bleeding risk with traditional and newer oral anticoagulant drugs. MedSurg Matters!, 23(5), 14-15.

Goldstein, P.C. (20l5).Venous thromboembolic (VTE) prophylaxis: Part II--Challenges in the treatment of acute bleeding events and development of new thrombin and Factor Xa inhibitor antidotes. MedSurg Matters!, 24(4), 9-13.

Guyatt, G.H., Akl, E.A., Crowther, M., Gutterman, D.D., Schuunemann, H.J., & American College of Chest Physicians Antithrombotic Therapy and Prevention of Thrombosis Panel. (2012). Executive summary: Antithrombotic therapy and prevention of thrombosis (9th ed.): American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest, 141 (Suppl. 2), 7S-47S.

Kumar, R" Smith, R.E., & Henry, B.L. (2015). A review of and recommendations for the management of patients with life-threatening dabigatran-associated hemorrhage: A single-center university hospital experience. Journal of Intensive Care Medicine, (epub ahead of print), doi: 10.1177/0885066614527417

Levine, E. (2014). CHADS2 score for stroke risk assessment in atrial fibrillation. Retrieved June 1,2015, from article/2172597-overview

Lip, G.Y., Nieuwlaat, R., Pisters, R., Lane, D.A., & Crijns, H.J. (2010). Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: The euro heart survey on atrial fibrillation. Chest, 137(2), 263-272.

Mohrien, K., Oliphant, C.S., & Self, T.H. (2013). Drug interactions with novel oral anticoagulants: gp and CYP3A4 effects. Consultant, 53(12), 918-919.

Patanwala, A.E., Acquisto, N.M., & Erstad, B.L. (201 I). Prothrombin complex concentrate for critical bleeding. Annals of Pharmacotherapy, 45(7-8), 990-999.

Perlstein, I., Wang, Z., Song, Y., Wang, J., Bedford, B., Chang, M., ... Frost, C. (2014, December 8). Reversal of apixaban anticoagulation by 4Factor Prothrombin Complex Concentrates (PCC) in healthy subjects. Paper presented at the 56th Annual Meeting of the American Society of Hematology, San Francisco, CA (Session 332). Retrieved December 10, 2014, from ash/2014/webprogram/start.html

Pisters, R., Lane, D.A., Nieuwlaat, R., de Vos, C.B., Crijns, H., & Lip, G.Y. (2010). A novel user-friendly score (HAS-BLED) to assess I-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest, 138(5), 1093-1100. doi: 10.1378/chest. 100134

Vilchez, J.A., Gallego, P.,& Lip, G.Y. (2014). Safety of new oral anticoagulant drugs: A perspective. Therapeutic Advances in Drug Safety, 5(1), 8-20

Perry C. Goldstein, MSN, RN, CMSRN, PCCN.TNCC, is a Staff Nurse, Critical Care Unit (CCU), Sumner Regional Medical Center, Gallatin, TN. He is a member of the MedSurg Matters! Editorial Committee.

Heather D. Hale, BSN, RN, CCRN, is a Staff Nurse, Critical Care Unit (CCU), Sumner Regional Medical Center, Gallatin, TN.
Table 5.
Pharmacokinetics (PK) and Pharmacodynamics (PD) of the NOACs
Compared to Warfarin

Characteristics              Warfarin       Dabigatran      Apixaban

Protein binding (%)             99              35             87

Half-life: [tl/2 (hours)]     20-60            7-17           8-15

(1) Reversal of              FFP/PCC     PCC Idarucizumab      PCC
Bleeding Events             Vitamin K+      Dialysis+

Metabolism/elimination      100% liver      80% renal       25% renal
                                            20% liver       75% fecal

Food interaction               Yes              No             No

Liver Substrates CYP         2C9, 3A4           No             3A4

Substrate P-gp                  No             Yes             Yes

Characteristics             Rivaroxaban   Edoxaban

Protein binding (%)             95           54

Half-life: [tl/2 (hours)]      7-13         9-11

(1) Reversal of                 PCC          PCC
Bleeding Events              Andexanet    Aripazine

Metabolism/elimination       33% renal    35% renal
                             67% liver    65% liver

Food interaction                No           NR

Liver Substrates CYP         3A4, 2J2        3A4

Substrate P-gp                  Yes          Yes

Key: CYP = cytochrome P proteins. Human CYPs are primarily membrane-
associated proteins located either in the inner membrane of
mitochondria or in the endoplasmic reticulum of cells. CYPs
metabolize thousands of endogenous and exogenous chemicals including
medications. FFP = fresh frozen plasma. NR = not researched. PCC =
prothrombin complex concentrate. P-gp = permeability glycoprotein,
also known as multidrug resistance protein I, an important protein of
the cell membrane that pumps foreign substances out of cells.

(1) As of January 6,2015, there are no licensed, FDA approved
medications for reversal of Factor I la and Factor Xa oral
anticoagulants. The suggestions for reversal of acute bleeding events
listed above are based upon preliminary available data from Phase II/
III studies and case reports in the medical literature, based on
physician clinical judgment. Refer to references above and also Table
3 in Part II.

Sources: Adapted from Dager,20l I; Kumar, Smith,& Henry,2015;
Patanwala, Acquisto,& Erstad, 2011;Vilchez,Gallego,& Lip,2014.
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Title Annotation:Drug Update
Publication:MedSurg Nursing
Article Type:Report
Date:Sep 1, 2015
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