Cases & Commentaries

New Oral Anticoagulants

Spotlight Case
Commentary By Margaret C. Fang, MD, MPH

Case Objectives

  • Review properties of newer target-specific oral anticoagulants (TSOACs) such as dabigatran, rivaroxaban, and apixaban.
  • State key perioperative considerations related to TSOAC use.
  • Describe potential errors associated with use of TSOACs.
  • List best practices for individuals and institutions that may reduce the frequency of TSOAC errors.

Case & Commentary—Part 1

A 39-year-old woman with a history of deep venous thrombosis (DVT) underwent an uncomplicated knee replacement. For pain control after surgery, an epidural catheter was placed. The patient's pain was well controlled with the catheter, which was managed by the pain service at this hospital. (Often used for pain control after orthopedic surgery procedures of the lower extremities, epidural catheters infuse analgesics such as lidocaine or opioids into the epidural space around the spinal cord. Anticoagulants are contraindicated at the time of insertion or removal due to bleeding risk.)

The patient had been on rivaroxaban (a relatively new oral anticoagulant) as treatment for her DVT before admission, and thus the discontinuation of anticoagulation placed her at high risk for recurrent DVT or pulmonary embolism. Per standard protocol, she was given enoxaparin (an anticoagulant injected subcutaneously) after surgery as a "bridge" until she could resume her oral anticoagulant. On the second hospital day, she was started on her outpatient dose of rivaroxaban.

For the past 60 years, vitamin K antagonists such as warfarin sodium have been the only available oral anticoagulant medications. More recently, target-specific oral anticoagulants (TSOACs) have become available for the treatment and prevention of thromboembolism and currently make up approximately 20% of new anticoagulant prescriptions.(1-4) There are currently three FDA-approved TSOACs: the direct thrombin inhibitor dabigatran (Pradaxa) and two factor Xa inhibitors, rivaroxaban (Xarelto) and apixaban (Eliquis). TSOACs work further down the clotting cascade and have more specific targets of inhibition than warfarin, leading to several advantages: fixed-dose oral dosing, fewer drug–drug and dietary interactions, and no need for routine coagulation monitoring (Table).(5,6) At present, all three are approved for use in preventing stroke in patients with atrial fibrillation. Rivaroxaban is also approved for the treatment and prevention of venous thromboembolism, such as in the case of this patient. We do not have information to explain why she was taking rivaroxaban instead of warfarin, but patients and providers may sometimes prefer using TSOACs due to the ease of administration and to avoid the monitoring needed when taking warfarin. The rivaroxaban was appropriately held before her surgery and then restarted on the second hospital day, presumably when the surgeon believed the risk of bleeding was low enough to tolerate anticoagulation.

Data from large randomized trials comparing TSOACs to warfarin largely conclude that TSOACs are at least as effective as warfarin in patients with atrial fibrillation and venous thromboembolism, and have similar, if not lower rates, of serious hemorrhagic complications (e.g., intracranial hemorrhage, gastrointestinal bleeding).(1,2) TSOACs all result in an increased risk for hemorrhage but, unlike warfarin, have no clinically-proven antidotes as of yet. In other words, there is no proven way to reverse the anticoagulation for any of the TSOACs. Patients who orally ingest a TSOAC are actively anticoagulated within several hours and, because the half-life of TSOACs is considerably shorter than that of warfarin, most of the anticoagulant effect will typically wear off within 1–2 days.(5) TSOACs are cleared, to varying degrees, by the kidneys, and patients with impaired renal function were largely excluded from clinical trials. Renal insufficiency can delay clearance of anticoagulant effect and TSOACs are not recommended in patients with severe renal insufficiency (e.g., creatinine clearance

Case & Commentary—Part 2

A few hours after receiving her third dose of rivaroxaban, the fellow on the pain service came to remove the epidural catheter. As was his usual practice, he scanned the medication list to be sure the patient was not on enoxaparin or warfarin or other traditional anticoagulants, but he did not review the rest of the list. He removed the epidural catheter while the patient was receiving treatment doses of rivaroxaban, placing her at very high risk for bleeding and the development of an epidural hematoma (the guidelines at this hospital stated that epidural catheters should not be removed for at least 24 hours following a dose of rivaroxaban).

Later, when writing his note about the procedure, he glanced at the medication list and noticed the patient was on rivaroxaban. He immediately examined the patient who was feeling well and had no back pain or weakness. The surgical team and pain service disclosed the error to the patient and monitored her very closely for the development of any complications. Fortunately, the patient did not have any apparent bleeding and was discharged in good condition.

Because TSOACs have only had FDA approval for 2–3 years, many clinicians may be unfamiliar with their use and properties. There is especially little information about the optimal management of TSOACs around the time of invasive procedures.(7) Patients undergoing neuraxial anesthesia (e.g., the epidural catheter used in this case) are at risk for developing rare but devastating bleeding around the spinal cord when exposed to anticoagulants. Recent guidelines from the American Society of Regional Anesthesia and Pain Medicine recommend that TSOACs be stopped for 2–4 days (depending on which of the three was used) before initiation of neuraxial anesthesia, and recommend against administration of a TSOAC while a catheter is in place, if possible, or to delay removal of a catheter until the anticoagulant effect is minimal.(8,9) Resumption of TSOACs should not be attempted for at least 6 hours after a catheter is removed. Individual institutions may have slightly different recommendations.

Although this patient did not experience any harm, the above situation would be characterized as a near miss. Two factors increased the likelihood of error in this situation: (i) the limited clinical experience with TSOACs among many clinicians; and (ii) the lack of a "safety net" system in place that could systematically identify and potentially catch errors related to high-risk medications.

Common Errors Related to TSOAC Use

A number of potential errors may occur related to TSOAC use.(10) The first is prescribing to inappropriate patients. Examples include prescribing TSOACs to a patient with severe renal insufficiency or using TSOACs for non-approved indications (e.g., mechanical heart valves). TSOACs may also not be appropriate for patients who have a very high bleeding risk, such as in the situation above or in patients with recent large hemorrhage at risk for recurrent hemorrhage.

Another potential error is inappropriate dosing or administration. TSOACs vary by their pharmacokinetics and elimination half-lives, and clinicians may not be aware of when to stop or start these medications in specific clinical situations, such as the perioperative period. In addition, unlike warfarin, which has a long half-life (thus patients remain anticoagulated even if a dose is missed), a missed dose of a TSOAC can be devastating because of these agents' relatively short half-lives. TSOACs now have black-box warnings informing clinicians that thromboembolism risk increases with abrupt discontinuation of the medication.(11)

Inappropriate monitoring also creates potential for error. Clinicians may inappropriately order coagulation tests that do not correlate with TSOAC effect. For example, commonly obtained tests for warfarin or heparin, including the prothrombin time or partial thromboplastin time, do not accurately measure TSOAC activity. Or, they may also fail to order TSOAC-specific tests when such tests are indicated, as in situations in which it is important to assess residual anticoagulant effect. For example, obtaining a thrombin time may be appropriate to determine whether there is residual dabigatran effect in a patient who did not remember when he last took his medication (Table).

Institutions should consider implementing interventions that address some of these common errors related to TSOAC use. Promoting awareness of new guidelines and updating medical knowledge among clinicians is certainly a component of effective interventions but is rarely sufficient to drive behavior change on a large scale.(12,13) Implementing system-level interventions, such as incorporating best practice or preferred prescribing recommendations into standardized order-sets or workflows, are considerably more effective than education alone. Information technology–based solutions, such as computerized "best practice alerts" that appear when a TSOAC is prescribed to patients with contraindications, can also help catch errors. Effective quality improvement interventions must also be supported by regular auditing of clinical practice paired with feedback to services and clinicians.

In the above case, the error may have been prevented if an automated best practice alert appeared when the clinician tried to order an anticoagulant in a patient with an epidural catheter. Ideally, institutions should be proactive about identifying problem areas related to high-risk medications (e.g., anticoagulants), performing periodic assessments of clinical practice, and developing system-level interventions to reduce the likelihood of errors where warranted. Often, these interventions require multidisciplinary input from medicine, nursing, and pharmacy.

Take-Home Points

  • Target-specific oral anticoagulants (TSOACs) have become viable alternatives to conventional oral anticoagulants and have the advantages of fixed-dose oral dosing, relatively rapid onset and offset, and fewer drug–drug interactions compared with warfarin.
  • Common errors related to TSOAC use include prescribing to inappropriate patients, recommending an inappropriate dose or administration, and inappropriate monitoring.
  • Clinicians should be particularly cautious about administering TSOACs to patients at high risk for bleeding, including those undergoing neuraxial anesthesia (e.g., an epidural catheter).
  • The rapidly evolving field of knowledge related to the use of TSOACs highlights the importance of developing institutional systems to improve awareness of these new agents and incorporate best practice standards into clinical workflow.

Margaret C. Fang, MD, MPH

Associate Professor of Medicine

Medical Director, UCSF Anticoagulation Clinic

University of California, San Francisco

Faculty Disclosure: Dr. Fang has declared that neither she, nor any immediate member of her family, has a financial arrangement or other relationship with the manufacturers of any commercial products discussed in this continuing medical education activity. In addition, the commentary does not include information regarding investigational or off-label use of pharmaceutical products or medical devices.

References

1. Mantha S, Ansell J. An indirect comparison of dabigatran, rivaroxaban and apixaban for atrial fibrillation. Thromb Haemost. 2012;108:476-484. [go to PubMed]

2. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ. 2012;345:e7498. [go to PubMed]

3. Kirley K, Qato DM, Kornfield R, Stafford RS, Alexander GC. National trends in oral anticoagulant use in the United States, 2007 to 2011. Circ Cardiovasc Qual Outcomes. 2012;5:615-621. [go to PubMed]

4. Xu Y, Holbrook AM, Simpson CS, Dowlatshahi D, Johnson AP. Prescribing patterns of novel oral anticoagulants following regulatory approval for atrial fibrillation in Ontario, Canada: a population-based descriptive analysis. CMAJ Open. 2013;1:E115-E119. [Available at]

5. Cabral KP. Pharmacology of the new target-specific oral anticoagulants. J Thromb Thrombolysis. 2013;36:133-140. [go to PubMed]

6. Mani H, Kasper A, Lindhoff-Last E. Measuring the anticoagulant effects of target specific oral anticoagulants—reasons, methods and current limitations. J Thromb Thrombolysis. 2013;36:187-194. [go to PubMed]

7. Connolly G, Spyropoulos AC. Practical issues, limitations, and periprocedural management of the NOAC's. J Thromb Thrombolysis. 2013;36:212-222. [go to PubMed]

8. Horlocker TT, Wedel DJ, Rowlingson JC, et al. Regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy: American Society of Regional Anesthesia and Pain Medicine Evidence-Based Guidelines (Third Edition). Reg Anesth Pain Med. 2010;35:64-101. [go to PubMed]

9. Gogarten W, Vandermeulen E, Van Aken H, Kozek S, Llau JV, Samama CM; European Society of Anaesthesiology. Regional anaesthesia and antithrombotic agents: recommendations of the European Society of Anaesthesiology. Eur J Anaesthesiol. 2010;27:999-1015. [go to PubMed]

10. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med. 2012;366:864-866. [go to PubMed]

11. MedWatch Safety Alert. Pradaxa (dabigatran etexilate mesylate) capsules. Rockville, MD: US Food and Drug Administration; April 2013. [Available at]

12. Gupta N, Sliwka D, Fang MC. Transitions in care: inpatient anticoagulation. In: Fang MC, ed. Inpatient Anticoagulation. 1st ed. Hoboken, NJ: Wiley-Blackwell; 2011:61-375. ISBN: 9780470602119. [Available at]

13. Maynard G, Jenkins I, Clay B, Montazeri M, Humber D. Optimizing inpatient anticoagulation: strategies for quality improvement. In: Fang MC, ed. Inpatient Anticoagulation. 1st ed. Hoboken, NJ: Wiley-Blackwell; 2011:377-414. ISBN: 9780470602119. [Available at]

Table

Table. Indications, Dosing, and Monitoring for Anticoagulant Medications.

Drug FDA-approved indications Dosing Coagulation monitoring? Reversible?
Warfarin Atrial fibrillation Adjusted to target INR range PT/INR Yes
Prevention and treatment of VTE
Mechanical heart valves
Dabigatran Atrial fibrillation
  • 150 mg po BID
  • 75 mg po BID if CrCl 15–30 mL/min
None routinely needed. Thrombin time is sensitive to presence of dabigatran No proven antidotes
Rivaroxaban Atrial fibrillation
  • 20 mg po daily
None routinely needed. Anti-factor Xa level may detect anticoagulant activity No proven antidotes
Treatment of VTE
  • 15 mg po BID for the first 3 weeks of VTE, then 20 mg po daily
Prevention of VTE after arthroplasty
  • 10 mg po daily
Apixaban Atrial fibrillation
  • 5 mg po BID
  • 2.5 mg po BID if ≥ 2 of the following factors: age ≥ 80, weight ≤ 60 kg, serum Cr ≥ 1.5 mg/dL
None routinely needed. Anti-factor Xa level may detect anticoagulant activity No proven antidotes

Abbreviations:
VTE: venous thromboembolism. PT: prothrombin time. INR: international normalized ratio. CrCl: creatinine clearance.