Spotlight Case

1. Spotlight Case New Oral Anticoagulants

2. Source and Credits • This presentation is based on the December 2013AHRQ WebM&M Spotlight Case • See the full article at http://webmm.ahrq.gov • CME credit is available • Commentary by: Margaret C. Fang, MD, MPH, University of California, San Francisco • Editor, AHRQ WebM&M: Robert Wachter, MD • Spotlight Editor: Bradley A. Sharpe, MD • Managing Editor: Erin Hartman, MS

3. Objectives At the conclusion of this educational activity, participants should be able to: • Describe the 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

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

5. Case: New Oral Anticoagulants (2) The patient had been on rivaroxaban (a newer anticoagulant) as treatment for her DVT before admission, and thus was at high risk for recurrent DVT or pulmonary embolism in the absence of anticoagulation. Per standard protocol, she was given enoxaparin (an anticoagulant injected subcutaneously) after surgery, but on the second hospital day she was started on her outpatient dose of rivaroxaban.

6. Background For 60 years, vitamin K antagonists (e.g., warfarin sodium) were the only available oral anticoagulant medications More recently, target-specific oral anticoagulants (TSOACs) have become available for treatment and prevention of thromboembolism TSOACs currently make up ~20% of new anticoagulant prescriptions

7. Background (2) • TSOACs work further down the clotting cascade • There are currently three FDA-approved TSOACs: • Dabigatran(Pradaxa): a direct thrombin inhibitor • Rivaroxaban (Xarelto): a factor Xa inhibitor • Apixaban (Eliquis): a factor Xa inhibitor

8. Advantages to TSOACs • TSOACs have several advantages: • Fixed-dose oral dosing • Fewer drug–drug and dietary interactions • No need for routine coagulation monitoring • At present, all three are approved for use in preventing stroke in atrial fibrillation • Rivaroxaban is also approved for treatment and prevention of venous thromboembolism

9. TSOACs vs. Warfarin • Multiple large randomized controlled trials have been performed comparing TSOACs with warfarin • TSOACs are at least as effective as warfarin in patients with atrial fibrillation and venous thromboembolism • TSOACs have similar, if not lower, rates of serious hemorrhagic complications (e.g., intracranial hemorrhage, gastrointestinal bleeding)

10. Challenges With TSOACs • Unlike warfarin, TSOACs have no clinically proven antidotes yet—there is no way to reverse anticoagulation for any TSOACs • Patients who orally ingest a TSOAC are actively anticoagulated within several hours • Because the half-life of TSOACs is shorter than warfarin, most of the anticoagulant effect will typically wear off within 1–2 days • As TSOACs are cleared by the kidney, they are not recommended in patients with severe renal insufficiency

11. TSOACs in This Case The case did not contain information explaining why this patient was taking rivaroxaban instead of warfarin However, patients and providers sometimes prefer using TSOACs due to ease of administration and to avoid monitoring needed with warfarin The patient's rivaroxaban was appropriately held prior to surgery and then restarted on hospital day 2, presumably when the surgeon felt the risk of bleeding was low enough to tolerate anticoagulation

12. Case: New Oral Anticoagulants (3) A few hours after receiving her third dose of rivaroxaban, the pain service fellow came to remove the epidural catheter. As was his usual practice, he scanned the medication list to be sure she 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 development of an epidural hematoma (guidelines at this hospital stated that epidural catheters should not be removed for at least 24 hours following a dose of rivaroxaban).

13. Case: New Oral Anticoagulants (4) Later when writing his note about the procedure, the fellow 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.

14. TSOACs and Invasive Procedures Because TSOACs have only had FDA approval for 2–3 years, clinicians may be unfamiliar with their use and properties There is especially little information about optimal management of TSOACs around the time of invasive procedures

15. TSOACs and Neuraxial Anesthesia Patients undergoing neuraxial anesthesia (such as the epidural catheter in this case) are at risk for rare but devastating bleeding around the spinal cord when exposed to anticoagulants The risk is increased during insertion and removal of the epidural catheters

16. TSOACs and Neuraxial Anesthesia (2) 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 3 was used) prior to initiation of neuraxialanesthesia These guidelines recommend against use of a TSOAC while a catheter is in place if possible, or to delay removal of a catheter until the anticoagulant effect is minimal

17. Near Miss in This Case • The patient did not experience harm, but this was a near miss • Two factors increased the likelihood of error in this situation: • The limited clinical experience with TSOACs among many clinicians • The lack of a "safety net" system in place that could systematically identify and potentially catch errors related to high-risk medications

18. Common Potential Errors With TSOAC Use • Prescribing to inappropriate patients • Those with severe renal insufficiency • Those with very high bleeding risk • Those with recent large hemorrhage at risk for recurrent hemorrhage • For non-approved indications (such as mechanical heart valves)

19. Common Potential Errors With TSOAC Use (2) • Inappropriate dosing or administration • TSOACs have different half-lives and clinicians may not know when to stop or start them in specific clinical situations • Given relatively short half-lives, a missed dose of TSOAC can be devastating as the anticoagulant effect may go away quickly • TSOACs now have black-box warnings informing clinicians that thromboembolism risk increases with abrupt discontinuation

20. Common Potential Errors With TSOAC Use (3) • Inappropriate monitoring • Clinicians may inappropriately order coagulation tests that do not correlate with TSOAC effect • Clinicians may also fail to order TSOAC-specific tests when such tests are indicated

21. Institutional Responsibility Institutions should consider implementing interventions that address 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 rarely sufficient to drive behavior change on a large scale

22. Institutional Responsibility (2) Best practice or preferred prescribing recommendations should be incorporated into standardized order-sets or workflows It may be useful to have "best practice alerts" that appear when a TSOAC is prescribed to patients with contraindications Effective quality improvement interventions must also be supported by regular auditing of clinical practice paired with feedback to services and clinicians

23. This Case • This error may have been prevented if an automated best practice alert had appeared when the clinician tried to order an anticoagulant in a patient with an epidural catheter • Institutions should be proactive about • Identifying problem areas related to high-risk medications (such as anticoagulants) • Performing periodic assessments of clinical practice • Developing system-level interventions to reduce the likelihood of errors where warranted • Such interventions often require multidisciplinary input from medicine, nursing, and pharmacy

24. Take-Home Points • TSOACs have become viable alternatives to conventional oral anticoagulants and have 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) • Rapidly evolving knowledge related to TSOAC use highlights the importance of developing institutional systems to improve awareness of these new agents and incorporate best practice standards into clinical workflow