36C25819R0003-025.docx

APPENDIX A

ANTICOAGULATION PHARMACY CLINIC

1. PURPOSE: To outline anticoagulation pharmacy clinic procedures that support Phoenix VA Health Care System (PVAHCS) Anticoagulation Therapy Management (ATM) Policy Memorandum No. 00-10.

2. DEFINITIONS:

a. Algorithm: refers to a standardized care process which outlines steps used to manage a patient’s anticoagulation therapy and is utilized across the PVAHCS. All algorithms will be evidence-based, approved by the Pharmacy and Therapeutics (P&T) Committee and Clinical Executive Board (CEB). An algorithm may be supported by protocols (for example, unfractionated heparin protocols by nursing staff) or Standard Operating Procedures (SOPs). Any actions or processes outlined in algorithms or protocols must be within the scope of practice of the individual performing the function and competency must be assessed on an ongoing basis as appropriate.

b. Anticoagulant: refers to a medication that inhibits blood coagulation. Anticoagulants include warfarin, unfractionated heparin, anti-Xa agents, low molecular weight heparin, and oral direct thrombin inhibitors. Medications which primarily inhibit platelet function are not included in the anticoagulant definition.

1) Anti-Xa Agents: Oral or injectable medications that inhibit the coagulation cascade through inhibition of Factor Xa. Oral examples include the Direct Oral Anticoagulants (DOACs) rivaroxaban (Xarelto®), apixaban (Eliquis®), and edoxaban (Savaysa®). Injectable examples include fondaparinux sodium (Arixtra®)

2) Low Molecular Weight Heparins (LMWH): Injectable medications that inhibit the coagulation cascade primarily through their effect on Factor Xa, but also to a lesser degree on Thrombin (Factor IIa). Examples include enoxaparin sodium (Lovenox®) and dalteparin sodium (Fragmin®).

3) Oral Direct Thrombin Inhibitors: Oral medications that inhibit the coagulation cascade through direct inhibition Thrombin (Factor IIa). Examples include dabigatran etexilate (Pradaxa®).

c. Anticoagulation Management Program (AMP): this is a coordinated program where anticoagulation providers manage anticoagulants for inpatients and outpatients within PVAHCS. In addition to the clinical practice aspect, the program also encompasses broader functions including coordinating policy and quality assurance relevant to anticoagulation management at the PVAHCS.

d. Anticoagulation Provider: refers to a provider who is currently trained and skilled in in managing anticoagulant therapy. VHA Directive 1033 outlines anticoagulation providers who may be clinical pharmacists, Advanced Practice Registered Nurses (APRN), physician assistants, and physicians. The anticoagulation provider is an active member of the anticoagulation management program, responsible to monitor the quality of his or her clinical practice, and has prescriptive authority defined in their scope of practice or clinical privileges that includes anticoagulants.

e. Anticoagulation Program Manager: is a Clinical Pharmacy Specialist that serves as a leader and information resource for the anticoagulation management program. He/she is responsible for ensuring that the program meets all elements in this policy. The anticoagulation program manager collaborates with other services to ensure that PVAHCS is compliant with standards outlined in VHA directive 1033. The anticoagulation program manager is generally a Clinical Pharmacy Specialist with a scope of practice, however other providers may be designated for this role at the PVAHCS.

f. Pharmacy Anticoagulation Champion: is an anticoagulation provider, generally a Clinical Pharmacy Specialist that serves to advocate for and support anticoagulation initiatives in the work group and at the PVAHCS.

g. Anticoagulation Support Staff: refers to a group of professionals assigned to the anticoagulation management program who perform day-to-day operational support functions under the supervision of anticoagulation program manager. Anticoagulation support staff may include, but are not limited to, pharmacy technicians, nurses, health technicians, and clerical associates. At the PVAHCS, anticoagulation support staff shall:

1) assist with many of the technical issues associated with the anticoagulation management program under the supervision of an anticoagulation provider,

2) have functional statements, coupled with a competency assessment that accurately reflects the job responsibilities and tasks they perform, and

3) answer and triage patient telephone calls, contact patients who have missed appointments, send letters to patients, communicate with outside laboratories, and other similar tasks

4) other duties as assigned.

h. International Normalized Ratio (INR): refers to a standardized measure of the PT, which is used to determine the clotting tendency of blood for a patient receiving warfarin therapy. The INR is the ratio of a patient's PT to a normal (control) sample, raised to the power of the International Sensitivity Index (ISI) value for the reagent system used.

i. International Sensitivity Index (ISI): is a measure of Thromboplastin sensitivity to an international standard. Each lot number of Thromboplastin used in Prothrombin or INR testing is assigned its own unique ISI value from the manufacturer.

j. Parent Facility: refers to PVAHCS with a three-digit Station Number 644 and includes all community clinics, outreach clinics and other locations where anticoagulation service is delivered to Veterans.

3. POLICY: This policy will support all elements of the Anticoagulation Therapy Management Program requiring patients prescribed anticoagulants by PVHCS prescribers to be monitored to reduce the likelihood of patient harm and to ensure compliance with:

a. High-Risk medication safety requirements.

b. VHA Directives 1033, 1014, 1069, 1070 and VHA Handbook 1108.03;

c. ISMP and Joint Commission High-Alert medication safety;

d. Guidance from the Criteria for Use (CFU) established by the National VA Pharmacy Benefits Management (PBM) group;

e. Applicable clinical practice guidelines; and

f. With the recommendations by expert medical opinion (rare diseases or unique clinical cases) or other governing bodies (DHHS) when applicable.

This policy applies to all PVAHCS facilities and affiliated medical staff who prescribe and/or administer medications. This includes, but not limited to physicians, physician assistants, clinical pharmacists, advance practice registered nurses, unit nurses or equivalents, and trainees. Certain section of this procedural policy may apply to other staff, who also provide direct or indirect patient care, as determined by Veterans Health Administration (VHA) and/or PVAHCS. To avert patient harm, minimize therapeutic and communications issues, this policy DOES NOT apply to:

g. non-VA prescribers, with or without affiliation with PVAHCS, who prescribe anticoagulants and follow patients independently; this also includes providers under “Choice Program”, contract clinics or other programs;

h. patients enrolled in anticoagulation related research programs or receiving investigational anticoagulation pharmacotherapies;

i. traveling Veterans who are managed by other VA Medical Centers;

j. any other situations, as determined by the PVAHCS.

4. PROCEDURES:

a. All patients receiving chronic oral therapeutic anticoagulation therapy will be managed through Anticoagulation Therapy Management (ATM) to comply with the VHA Directive 1033 and patient safety and accreditations standards.

b. The ordering provider will place an “Pharmacy outpatient anticoagulation consult” for patients who are being prescribed or discharged on warfarin and a Prior Authorization Drug Request for patients prescribed or discharged on a DOAC for the patient to be enrolled in the Outpatient Clinical Pharmacy Anticoagulation clinic. AMP staff will review and answer these consults to ensure appropriate documentation of pertinent information in the electronic medical record (EMR).

c. The Clinical Pharmacy Specialists (CPSs) in AMP, through the authority of their scopes of practice, will assist providers with agent selection when possible or when requested, and may change/modify therapies based on the best available guidance and formulary preference consistent with Anticoagulation Therapy Management (ATM) and VHA Directive 1033.

d. Patients and or caregivers will receive in-depth education about their respective therapies either by Inpatient Clinical Pharmacy staff (for patients admitted at the time of therapy initiation), ED CPS or AMP staff (for outpatients) as delineated under item procedures in section 4, section “b” of Anticoagulation Therapy Management (ATM) (Policy Memorandum No. 00-10).

e. Face-to-face appointments, telephone contact, and letters will be used for routine patient interactions. When telephone messages are left, a letter will be sent to reinforce the therapeutic plan.

f. Patients will be given the direct telephone number of the Anticoagulation clinic. The voicemail greeting will instruct the patient of the service’s regular business hours, when they may expect to receive a call back, and to seek emergency medical attention if there are concerns about bleeding or thrombotic complications. After hours, the patients may choose to leave a message for non-urgent matters. AMP staff will contact patients who leave a message the next business day.

g. Patient’s failure to comply with recommended therapy and monitoring will result in the following procedures:

1) Patients will be contacted by telephone or letter (depending on urgency) for rescheduling once the missed appointment is noted.

2) If the clinic is unable to contact patient by telephone, the patient will be mailed a letter advising them to reschedule an appointment. Clinic will also continue to attempt contact via telephone.

3) In the event of patient’s continued failure to report and continued inability to contact patient by telephone, the emergency contact and/or next of kin will be contacted to place the clinic in contact with the patient.

4) Should these efforts remain futile, the Primary Care Provider, appropriate specialist, and/or Medical Director of the AMP will be contacted about the risk vs. benefit of continued anticoagulation therapy in the absence of appropriate monitoring.

h. Patients will be considered for discharge from AMP and their prescribed anticoagulant will be discontinued following:

1) completion of therapy;

2) request by the Primary Care Physician (PCP0 or patient;

3) emergence of dual-care situations;

4) failure to comply with the therapy including habitual medication non-compliance and instructions;

5) failure to comply with the required monitoring on >2 consecutive occasions;

6) time is greater than 90 days from last INR, despite multiple attempts to reschedule and communicate with patient

7) as determined by the Anticoagulation Program Manager.

i. Management of Warfarin:

1) Warfarin will be managed using the algorithms published by the National VA PBM CPPO (attached). Deviations from these algorithms are expected and will be based on the clinical judgement of the individual AMP staff member.

2) Therapeutic INR Results:

a) Patients with INR results in the therapeutic range on a stable dose will be mailed a letter advising of their INR result. The following verbiage will be included as well as contact information for the respective clinics: If you have any questions, notice any signs of bleeding, are taking any new medications, or have stopped taking any medications, or if you are taking a different Warfarin (Coumadin) dose than indicated above, please notify the Anticoagulation Clinic with current telephone number.

b) Repeat INR and anticoagulation clinic follow up will occur at appropriate intervals consistence the best available guidance based on recommendations from guidelines or PBM, or as determined by Anticoagulation Program Manager.

3) Minimally Sub-/Supra-therapeutic INR results:

a) Patients who have been recently well controlled and present with INR results within 0.3 of the limits of the target range will generally be treated the same as patients with therapeutic INR results.

b) These patients will be followed more closely with repeat INR – generally not to exceed 2 weeks.

4) Non-therapeutic INR results (Sub- or Supratherapeutic, but INR less than 4.6):

a) Attempts will be made to contact the patient by telephone to conduct an interview.

b) If contact is made, clinical interview will be conducted and instructions for warfarin dosing and next appointment date will be given to the patient or caregiver.

c) If there is no answer:

1) A detailed message will be left on an answering device (if present) and a letter will be sent for patient to contact clinic as soon as possible.

2) If there is no answering device or if otherwise clinically warranted, continued attempts at contact will be made throughout the day.

3) If AMP staff feel it necessary, contact may be made with the Primary Care Provider or other relevant providers and and/or a request for an in-home wellness check.

d) If the clinic is unable to make contact, a letter will be sent and will include instructions for the patient to contact the clinic to update their contact information. Future appointments may be arranged as face-to-face until reliable telephone contact can be confirmed.

5) Critically-elevated INR results (INR greater than or equal to 4.6):

a) Laboratory service staff reports INR values of greater than or equal to 4.6 as “critically elevated”. During regular business hours, outpatients’ results are called to the AMP staff. ED results are called to the ED for a patient in the ED who will be discharged to the outpatient setting. The ED provider must document in the CPRS provider note the following information:

(1) elevated INR value,

(2) action taken,

(3) follow-up required

(4) patients who are followed by the Phoenix VA Anticoagulation clinic will be monitored when the patient has a repeat INR drawn.

b) If contact is made, clinical interview will be conducted and instructions with therapeutic changes and next appointment date will be given to the patient or caregiver.

c) If the patient or caregiver cannot be reached, a message will be left advising the patient to hold warfarin, contact the clinic, and that they have a low threshold for presenting for emergency medical care should bleeding occur.

d) Continued attempts to contact will be made at all listed telephone numbers throughout the day. If the clinic remains unable to contact the patient, emergency contacts and next-of-kin will be contacted to assist in locating the patient and to assure safety. If the clinic is unable to reach the patient, continued attempts will be made the following day.

e) If the above attempts are unfruitful, the anticoagulation clinic will send a letter advising of the risk and urging the patient to contact the clinic immediately. If AMP staff feel it necessary, contact may be made with the PCP or other relevant providers and and/or a request for an in-home wellness check. Involvement of the local Police Department for an in-home Wellness Check may be pursued if clinically warranted at any time.

f) Depending on the severity of the INR elevation and the clinical situation, contact may be made with the PCP or other relevant providers. The patient may be given vitamin K and/or advised to present to the emergency room for evaluation.

g) In general, patients will be evaluated for a new or worsening anemia (Hemoglobin/Hematocrit) when the INR is repeated after a critically-elevated INR.

6) The AMP staff will utilize the Anticoagulation Management Tool (AMT), a software tool available within the Computerized Patient Record System (CPRS) and designed to manage patients prescribed warfarin. The team will run a daily report of INR labs to act on and will run a weekly report of late follow up INR labs to capture patients who have not completed labs on the assigned date. This tool and process will minimize losing patients to follow-up, but a report will be run to proactively look for patients lost to follow-up and AMP support staff will routinely use this report.

7) Risks and benefits of warfarin will be assessed on an ongoing basis.

j. Management of DOACS:

1) AMP staff will routinely review all patients prescribed DOACs, assessing adherence to therapy as well as ensuring appropriate scheduling for monitoring. Technology and/or appointment scheduling will be used to track patients and prevent them from becoming lost to follow-up. In addition, AMP staff will limit refills as per professional discretion to ensure supplies will not last significantly beyond planned appointments for monitoring.

2) Labs will be obtained if felt to be clinically indicated. The AMP staff may choose to interview the patient (i.e., inquiring about adverse events, medication adherence) depending on the clinical scenario.

3) If the requested laboratory results are within normal limits (WNL) and stable and the patient is deemed “adherent” to therapy, the AMP staff may choose to contact the patient for interview and/or mail a letter advising of test results (with assessment), next laboratory appointment, and call-back information for the AMP.

4) If the requested laboratory tests are WNL and stable, but the patient is deemed non-adherent to therapy, the interview becomes more pertinent as the AMP staff needs to question and stress the importance of adherence, and document findings/education. The following procedures will be followed:

a) The AMP staff will attempt telephone contact for interview.

b) If contact cannot be made, a message will be left asking the patient to call the clinic with the clinic phone number.

c) AMP staff will continue attempts at contact throughout the day. If unable to contact by the end of the day, attempts will continue for up to three consecutive days.

d) If after three consecutive days the attempts at contact remain futile, a letter will be mailed advising of test results. The letter will include verbiage stressing the importance of adherence to therapy, and advising the patient to contact the clinic if any problems are noted, including (but not limited to) adverse events, problems w/ adherence, bleeding complications, etc. Letter may also advise the patient about discharge option from AMP.

5) If the requested laboratory tests are obtained and the results are deemed abnormal and a cause for clinical concern, the following procedures will be followed:

a) The AMP staff will attempt telephone contact for interviewing the patient. If contact cannot be made, a message will be left asking the patient to call the AMP urgently and list a good call-back number. Continued attempts at contact will be made throughout the day.

b) Depending on the level of clinical concern, the PCP, appropriate specialist, and/or emergency room physicians that are involved in the care of the patient will be added to the progress notes for engaging their clinical expertise and for providing situational awareness.

c) Risks and Benefits of DOAC therapy will be assessed on an ongoing basis.

k. Periprocedural Anticoagulation:

1) The AMP staff will partner with proceduralists and PCPs to manage anticoagulated patients with planned procedures, using the best available guidance to develop individual patient care plans.

a) Periprocedural interruptions of Warfarin: Once made aware of a planned procedure with the need for anticoagulation reversal, CPSs in AMP will critically evaluate patient- and procedure-specific bleeding and thrombotic risks and determine the need for “bridging” anticoagulation using guidance published by the VA PBM CPPO (attached) as well as other available guidance and discussion with the patient and providers (as appropriate).

b) Periprocedural interruptions of DOACs: Once made aware of a planned procedure with the need for anticoagulation reversal, CPSs in AMP will critically evaluate patient- and procedure-specific bleeding and thrombotic risks. They will also estimate the expected elimination half-life of the DOAC (driven largely by the patient’s renal function). Patients will then be given instructions to hold the DOAC for a sufficient time to allow for clearance of the drug. The attached “DOAC Interruption Guidance”, along with other available guidance will be used as reference.

5. RESPONSIBILITIES:

a. The Chief of Staff, Deputy Chief of Staff, Associate Director for Patient Care Services, and Chief of Pharmacy Service are jointly responsible for operationalizing of this procedural policy.

b. The Clinical Executive Board and the P&T Committee are responsible for altering, reviewing and approving procedures described in section 4. Anticoagulation Program Manager and will coordinate changes in this policy and ensure all procedures included herein are evidence-based and comply with VHA Directive 1033.

6. RESPONSIBLE BOARD: Pharmacy and Therapeutics

7. REFERENCES:

a. VHA Directive 1033, Anticoagulation Therapy Management.

b. VHA Directive 1070, Adverse Drug Event Reporting and Monitoring.

c. VHA Directive 2009-019, Ordering and Reporting Test Results.

d. VHA Handbook 1138.01, Patient self-testing for monitoring PT/INR

e. VHA Handbook 1100.19, Credentialing and Privileging.

f. VHA Handbook 1101.10, Patient Aligned Care Team (PACT) Handbook.

g. VHA Handbook 1101.11, Coordinated Care Policy for Traveling Veterans.

h. VHA Handbook 1106.01, Pathology and Laboratory Medicine Service Procedures.

i. VHA Handbook 1108.05, Outpatient Pharmacy Services.

j. VHA Handbook 1108.06, Inpatient Pharmacy Services.

k. VHA Handbook 1108.11, Clinical Pharmacy Services.

l. Antithrombotic Therapy and Prevention of Thrombosis, 9th edition: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST. 2012; 141(2): February Supplement.

m. National Patient Safety Goals, The Joint Commission Comprehensive Accreditation and Certification Manual, current edition.

n. VA PBM Criteria for Use – Anticoagulants

8. RESCISSION: None

9. ATTACHMENTS:

a. Appendix A

1) VA PBM CPPO Strong Recommendation Warfarin Algorithms

2) VA PBM CPPO Periprocedural Guidance

3) DOAC Interruption Guidance

10. FOLLOW-UP RESPONSIBILITY: Chief of Pharmacy

11. EXPIRATION DATE: January 2021

RIMAANN O. NELSON

Medical Center Director

Appendix A

a. VA PBM CPPO Strong Recommendation Warfarin Algorithms

b. VA PBM CPPO Periprocedural Guidance

c. DOAC Interruption Guidance image1.emf

PBM CPPO Strong Practice Recommended Warfarin Initiation Algorithm.pdf

VHA CPPO Pharmacy Benefits Management (PBM) Strong Practice Recommended Warfarin Management Algorithm (Initiation Phase of Therapy)

Step 1: Begin with 5 mg or 2 mg daily (if patient requires a lower dose).

Lower initial dosing may be appropriate based on the following patient characteristics:

Age (generally, frail elderly patients are more sensitive to warfarin) Weight (generally, low body weight or malnourished patients are more sensitive to warfarin) Past medical history (including liver dysfunction, heart failure, end-stage renal disease, hyperthyroidism, or recent major surgery) Social history (including alcohol and tobacco use) Interacting medications (prescription, herbal, and over-the-counter products)

Dietary habits and nutritional status (especially dietary vitamin K content) Acute illness (including loss of appetite, fever, vomiting, and diarrhea) Risk factors for bleeding (including bleeding disorder, history of bleeding, peptic ulcer disease, history of hemorrhagic stroke, high fall risk, and hypertension)

Step 2: Follow warfarin dosing adjustments based on INR results.

Measurement Day INR Action

Measure PT/INR on Day 1 Baseline INR Start patient on 2 to 5 mg depending on risk factors

Measure PT/INR on Day 3-4 <1.5 Increase weekly dose by 5-25%

1.5-1.9 No dosage change

2.0-2.5 Decrease weekly dose by 25-50%

>2.5 Decrease weekly dose by 50% and/or HOLD dose

Measure PT/INR on Day 5-7 <1.5 Increase weekly dose by 10-25%

1.5-1.9 Increase weekly dose by 0-20%

2.0-3.0 No dosage change

>3.0 Decrease weekly dose by 10-25% and/or HOLD dose

Measure PT/INR on Day 8-10 <1.5 Increase weekly dose by 15-35%

1.5-1.9 Increase weekly dose by 5-20%

2.0-3.0 No dosage change

>3.0 Decrease weekly dose by 10-25% and/or HOLD dose

Measure PT/INR on Day 11-14 <1.6 Increase weekly dose by 15-35%

1.6-1.9 Increase weekly dose by 5-20%

2.0-3.0 No Dosage Change

>3.0 Decrease weekly dose by 5-20% and/or HOLD dose

Adapted from: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM: Pharmacotherapy: A Pathophysiologic Approach, 8th Edition: www.accesspharmacy.com (Figure 26-8)

Additional Considerations:

If patient has not attained an in-range INR result by Day 14, continue Day 11-14 routine until INR is in-range.

Holding the dose may complicate efforts at dose-finding and is not usually necessary. In our opinion, it should be reserved for INR values above 5.0 in the initiation phase, when bleeding risk is thought to be very high. For less extreme INR elevations, a dose decrease should be sufficient, especially given that follow-up will be quite soon thereafter.

In some cases, the following may be considered: For patients sufficiently healthy to be treated as outpatients, we suggest initiating VKA therapy with warfarin 10 mg daily for the first two (2) days followed by dosing based on INR measurements (Grade 2C). [CHEST 2012]

When the patient has achieved three (3) in-range INR results, use the VISN 1 Anticoagulation Management Algorithm (Maintenance Phase of Therapy).

http://www.accesspharmacy.com/ image2.emf

PBM CPPO Strong Practice Recommended Warfarin Maintenance Algorithm.pdf

Continues on Next Page Revised July 3, 2014

VHA CPPO Pharmacy Benefits Management (PBM) Strong Practice Recommended Warfarin Management Algorithm (Maintenance Phase of Therapy) Disclaimer: This algorithm is for ongoing management of warfarin. As with any algorithm or guideline, the final decision must always rest with the clinical judgment of the responsible provider.

Goal of INR 2.0-3.0 INR Action ≤ 1.5 Increase weekly dose by 10-15%; repeat INR within 7 days.

1.51-1.79 If falling or low on two or more occasions, increase weekly dose by 5-10%; repeat INR in 7-14 days.

1.80-1.99 Consider not changing the dose unless a consistent pattern has been observed;1 repeat INR in 7-14 days.

2.00-3.00 (in-range)

No change in dose. Follow-up within 28 days. If INR has been in-range 3X consecutively, follow-up within 42 days.2

3.01-3.20 Consider not changing the dose unless a consistent pattern has been observed;1

3.21-3.69 Do not hold warfarin. If rising or high on two or more occasions, decrease weekly dose by 5-10%; repeat INR in 7-14 days.

3.70-4.99 Hold for 1 day and decrease weekly dose by 5-10%; repeat INR determination within 7 days.

5.00-9.99 Hold warfarin. Check INR within 5 days. When INR is therapeutic, restart at lower dose (decrease weekly dose by 10-15%). Check INR at least weekly until stable.

≥ 10.0 (without bleeding)

Hold warfarin and give oral vitamin K, 2.5 mg. Check INR at least weekly until stable.

Serious Bleeding Regardless of INR

Hold warfarin and refer patient to emergency department immediately.

Goal of INR 2.5-3.5 INR Action ≤ 1.5 Increase weekly dose by 10-15%; repeat INR within 7 days.

1.51-1.99 If falling or low on two or more occasions, increase weekly dose by 10-15%; repeat

2.00-2.29 If falling or low on two or more occasions, increase weekly dose by 5-10%; repeat

2.30-2.49 Consider not changing the dose unless a consistent pattern has been observed;1

2.50-3.50 (in-range)

No change in dose. Follow-up within 28 days. If INR has been in-range 3X consecutively, follow-up within 42 days.2

3.51-3.70 Consider not changing the dose unless a consistent pattern has been observed;1

3.71-4.19 Do not hold warfarin. If rising or high on two or more occasions, decrease weekly dose by 5-10%; repeat INR in 7-14 days.

4.20-4.99 Hold for 1 day and decrease weekly dose by 5-10%; repeat INR determination within 7 days.

5.00-9.99 Hold warfarin. Check INR within 5 days. When INR is therapeutic, restart at lower dose (decrease weekly dose by 10-15%). Check INR at least weekly until stable.

≥ 10.0 (without bleeding)

Hold warfarin and give oral vitamin K, 2.5 mg. Check INR at least weekly until stable.

Revised July 3, 2014

Serious Bleeding Regardless of INR

Hold warfarin and refer patient to emergency department immediately.

Disclaimer/Guide to Use: In a well-designed before and after trial, the use of this algorithm improved percent time in range (TTR) by 6%.3 While clinicians will override these recommendations at times, they should keep in mind that when this algorithm was tested, patients whose management conformed most closely to the algorithm had the best TTR.

Additional Recommendation: In addition to this algorithm, ACC clinicians are urged to avoid non-standard target INR ranges such as 2-2.5 or 1.8-2.5. The 2012 CHEST Guidelines state that there should be two target ranges in clinical practice: 2.5-3.5 for patients with mitral prosthetic valves and 2-3 for everyone else.4 In some instances, practitioners may chose a goal of 2.5-3.5 for patients with aortic prosthetic valves with additional risk factors. This is the recommendations from the most recent AHA guidelines and may be used at the recommendation of a referring provider.5 Other target ranges do not provide additional benefit and place patients at higher risk, and should be avoided.

References

1. Rose AJ, Ozonoff A, Berlowitz DR, Henault LE, Hylek EM. Warfarin dose management affects INR control. J Thromb Haemost. Jan 2009;7(1):94-101.

2. Rose AJ, Ozonoff A, Berlowitz DR, Ash AS, Reisman JI, Hylek EM. Reexamining the recommended follow-up interval after obtaining an in-range international normalized ratio value: results from the Veterans Affairs study to improve anticoagulation. Chest. Aug 2011;140(2):359-365.

3. Kim YK, Nieuwlaat R, Connolly SJ, et al. Effect of a simple two-step warfarin dosing algorithm on anticoagulant control as measured by time in therapeutic range: a pilot study. J Thromb Haemost. Jan 2010;8(1):101-106.

4. Whitlock RP, Sun JC, Fremes SE, Rubens FD, Teoh KH. Antithrombotic and thrombolytic therapy for valvular disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. Feb 2012;141(2 Suppl):e576S-600S.

5. Nishimura RA, Otto CM, Bonow RO, et al. 2014 AHA/ACC Guideline for the Management of Patients With Valvular Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. Circulation. Jun 10 2014;129(23):e521-643.

image3.emf

PBM-CPPO-Anticoagulation SME Strong Practice Clinical Recommendations for Warfarin Interruption 12-11-15.pdf

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 1

PBM-CPPO-Anticoagulation Subject Matter Expert Workgroup Clinical Guidance for Warfarin Interruption

Disclaimer: This document is intended to provide guidance for VA clinicians in the perioperative management of warfarin. Areas of uncertainty still exist and are noted throughout the document.

Exceptions to the recommendations will occur; the clinician should utilize this guidance and interpret it in the clinical context of the individual patient. Separate guidance will be released for how to perform a low molecular weight heparin (LMWH) bridge, and regarding interruptions of direct-acting oral anticoagulant (DOAC) therapy.

Bridge Therapy: For the purposes of this document, “Bridge” therapy is used to describe the application of a parenteral, short-acting anticoagulant for warfarin patients requiring short term, temporary interruption of anticoagulation for an invasive procedure. This document is not intended to address Perioperative VTE prophylaxis which should be provided when appropriate.

Statement of purpose: Due to the recent publication of several important studies, there has been a major shift in thinking about the perioperative management of anticoagulation. New evidence does not support many recommendations included in existing consensus guidelines such as the 2012 AT9 Guidelines. Because updated consensus guidance (such as from the AC Forum) may be months or years away from publication, the PBM-CPPO-Anticoagulation Subject Matter Expert (SME) Workgroup has developed clinical guidance that incorporates the updated evidence. It is important that all providers involved in managing perioperative anticoagulation be aware of the important changes. The Workgroup estimates that over 90% of patients receiving warfarin should no longer receive bridging, except under unusual circumstances and with appropriate justification. The large number of patients potentially affected by this change in practice represents an important safety concern that requires urgent and widespread communication of these changes to the field.

Levels of Evidence Cited in this Document1 Level A: Evidence from at least one high-quality randomized trial Level B: Evidence from at least one high-quality observational study Level C: Recommendation based solely upon expert opinion and/or pathophysiological principles; no supporting evidence from clinical studies.

Abbreviations:

AC Forum – The Anticoagulation Forum, a guideline-writing body ACCP – The American College of Chest Physicians, a guideline-writing body AF – atrial fibrillation AT9 – shorthand for the 2012 ACCP Antithrombotic 9 Guidelines CHADS2 – a score to risk-stratify patients with atrial fibrillation regarding risk of stroke CPPO – Clinical Pharmacy Program Office of VA PBM CVA – cerebrovascular accident (stroke) DOAC – direct-acting oral anticoagulant, such as dabigatran, rivaroxaban, or apixaban INR – International Normalized Ratio, a laboratory test to monitor anticoagulation with warfarin LMWH – low-molecular weight heparin SME – Subject Matter Experts

These levels of evidence are stated in the context of what is known about this topic. Other guidelines might require multiple high-quality randomized trials to constitute “A” level evidence, but given how little is known about this topic, a single high-quality trial constitutes “A” level evidence here.

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 2

TE – thromboembolism, including both arterial and venous thromboembolism TIA – transient ischemic attack, or a stroke that resolved before permanent damage was done VKA – vitamin K antagonist – usually warfarin VTE – venous thromboembolism, including pulmonary embolism and deep venous thrombosis

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 3

Executive Summary: Important New Material/Main Points The material in this section is original, and is not drawn from AT9.

1. New evidence has emerged that the practice of bridging causes net harm for the majority of patients who had been considered candidates for bridging according to the 2012 ACCP Antithrombotic Guidelines (AT9). The PBM-CPPO_Anticoagulation SME Workgroup estimates that approximately 90% of patients who receive anticoagulation with warfarin should no longer receive bridging except under unusual circumstances, and with appropriate justification.2

a. In general, bridging should no longer be offered to the great majority of patients with atrial fibrillation (AF; lower-risk group defined by CHADS2 scores 0-4,3 Level A Evidence4), Venous Thromboembolism (VTE) which occurred more than 3 months ago (Level B Evidence5), or mechanical aortic valves (Level B Evidence6).

i. Patients with unprovoked VTE 3-12 months ago may represent an intermediate category of risk, with lower risk of thrombosis than VTE within the past 3 months but higher risk of thrombosis than VTE more than a year ago. While evidence is lacking for how these patients should be managed, most experts in our group concurred that prophylactic-dose LMWH (rather than full treatment dose) would represent a reasonable option (Level C Evidence).

b. Bridging should still be considered for patients with mechanical mitral valves, atrial fibrillation with CHADS2 scores 5-6, atrial fibrillation with cerebrovascular accident (CVA) within the past 3 months, highly thrombogenic cancers currently under active treatment, and certain other patient groups (Level C Evidence).

However, even among these groups, bridging should no longer be automatic, and the risks and benefits must be considered carefully, taking into account both patient and procedure-related factors. The risks of bridging are likely to outweigh the benefits for at least some of these patients as well.

c. Bridging would still be recommended for most patients with VTE within the past 3 months, although even for these patients, the clinician should still give careful consideration to the relative risks and benefits, and for some patients, the risks will outweigh the benefits (Level B Evidence).

2. Despite the above, in our opinion, bridging should not be abandoned entirely. It is likely that there still are some clinical scenarios (possibly few) in which patients will receive net benefit from the practice. (Level C Evidence)

3. Above all, clinicians are encouraged to re-examine their practice, as a major change has occurred in the evidence. Given newly available evidence, in our opinion, continuing to follow the AT9 guidelines regarding bridging would no longer be appropriate. (Level A Evidence)

The 90% figure is based on the following: adding up patients with mitral mechanical valves, VTE within the past 3 months, and AF with CHADS2 scores 5-6 collectively constitutes less than 10% of patients receiving warfarin in an ACC.

Gage BF, et al. Validation of clinical classification schemes for predicting stroke: results from the National Registry of Atrial

Fibrillation. JAMA. 2001;285 (22):2864-70.

BRIDGE Trial, N Engl J Med, online before print. Also Circulation 2015;131:488-94.

Clark et al., JAMA Intern Med, online before print.

Kaiser Permanente, manuscript under review.

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 4

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 5

Brief Review of Recent Evidence

Since the release of AT9 in 2012, multiple new, important studies have greatly changed how the decision of whom to bridge should be viewed.

First, it is necessary to repeat the important fact that no study has ever shown a benefit from the practice of bridging, in terms of preventing thromboembolism, among any patient population. The entire practice of bridging, when done, has always been based solely upon expert opinion.

The BRIDGE Trial (N Engl J Med 2015;373:823) : BRIDGE enrolled 1,884 patients with AF on warfarin therapy, 97% of whom had CHADS2 scores from 1-4. Patients were randomized to receive LMWH bridging or no bridging during the perioperative period.

Arterial thromboembolism occurred in 4 patients who were not bridged (2 CVAs and 2 TIAs) and 3 patients who were bridged, meeting the preset criterion for noninferiority.

Major bleeding occurred in 29 patients who received bridging and 12 who did not (p = 0.005). Minor bleeding occurred in 187 bridging patients vs. 110 non-bridging patients (p < 0.001).

ORBIT-AF Registry Study (Circulation 2015;131:488): This study was based upon a prospective registry of AF patients in the United States. 2,803 interruptions of warfarin occurred, with bridging used in 24% of these instances. Bleeding events occurred in 5.0% of bridged vs. 1.3% of non-bridged patients (p < 0.001). Stroke or systemic embolism occurred in 0.6% of bridged patients and 0.3% of unbridged patients (p = 0.5).

The incidence of a composite endpoint (which included myocardial infarction, stroke, systemic embolism, major bleeding, hospitalization, or death within 30 days) was higher in bridged than non-bridged patients (13% vs. 6.3%, p < 0.001), mainly due to a higher rate of hospitalization. The study adjusted for covariates, although covariates were similar between groups.

Sub-analysis of RE-LY study (Thrombosis and Haemostasis 2015;113:625): The RE-LY study was a randomized trial comparing warfarin with dabigatran. The authors took advantage of the detailed prospective data collection to perform this analysis.

Anticoagulation was interrupted for 1,424 warfarin patients (27.5% of whom were bridged) and 2,709 dabigatran patients (15.4% of whom were bridged). In warfarin patients, bridging was associated with more major bleeding (OR 4.62, p < 0.001). In dabigatran patients, bridging was associated with more major bleeding (OR 3.68, p < 0.001). The overall rates of TE were low, with 7 events for warfarin/ bridged, 3 for warfarin/not bridged, 13 for dabigatran/bridged, and 5 for dabigatran/not bridged. TE was not reduced by bridging, and in fact bridged patients had a higher rate of TE. This difference achieved statistical significance only for the comparison of any TE among warfarin patients (more TE among those bridged, p = 0.007). The authors had planned to do a propensity-matched analysis based on bleeding and TE risk scores, but patients who did and did not receive bridging were already well-matched at baseline.

2012 Meta-analysis (Circulation 2012;126:1630): This meta-analysis included 33 observational studies and one randomized trial. These studies represented a total of 7,118 bridged and 5,160 non-bridged patients, who were receiving anticoagulation for

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 6 varied indications. Most included studies were of poor methodological quality.

Thromboembolic events occurred in 0.9% of bridged patients and 0.6% of non-bridged patients. Rates of overall and major bleeding were 13.1% and 4.2% among bridged patients, and 3.4% and 0.9% among non-bridged patients. Meta-analyses showed that bridging was not significantly different from non-bridging in terms of preventing thromboembolism, or TE (OR 0.80, 0.42-1.54), but was associated with significantly higher rates of overall bleeding (OR 5.40, 3.00-9.74) and major bleeding (OR 3.60, 1.52

– 8.50).

Kaiser Permanente VTE Study (JAMA Intern Med: epub ahead of print): This observational study included 1,178 patients receiving warfarin for long-term treatment of VTE. For 96% of these patients, the VTE was more than one year ago, with most of the remainder between 3-12 months ago. 31% of patients received bridging. Recurrent VTE occurred in 3 non-bridged and 0 bridged patients (p = 0.56). Clinically relevant bleeding occurred in 15 bridged vs. 2 non-bridged patients (p = 0.01).

Kaiser Permanente Mechanical Heart Valve Study (under review): This study is not yet published, and the AC SME Workgroup is not able to release details. However, the PBM-CPPO- Anticoagulation SME Workgroup can generally state that this study concords with the general pattern of all the other studies, in that bridging was associated with a markedly increased risk of bleeding, but no demonstrable benefit in terms of preventing TE. Most of the patients in this study had mechanical valves in the aortic and not the mitral position.

Summary of Evidence: Within the past year, several studies have been published which call into question the practice of bridging, at least for the majority of patients. For patients with AF, a high-quality randomized trial and a high-quality observational study both showed that the great majority of patients with AF experience net harm from bridging. A meta-analysis about bridging in AF, combining multiple small, low-quality studies, supports the same conclusion.

For patients with VTE, a high-quality observational study showed that the great majority of patients, especially those whose event was more than a year earlier, do not receive net benefit from bridging. For patients with mechanical aortic valves, a yet unpublished observational study suggests that patients do not receive net benefit from bridging. In all of these studies, bridging was associated with a greatly increased risk for major bleeding – usually about 5-fold.

None of these studies demonstrated any reduction in thromboembolism from bridging – let alone a reduction important enough to justify the increased bleeding. The RE-LY analysis also strongly suggests that bridging is not needed with target-specific anticoagulants – nor would it to necessary be expected to.

Limitations of Evidence: Studies were only adequately powered to exclude a fairly large clinical benefit from bridging, in terms of preventing thromboembolism (TE). Having sufficient power to exclude a small clinical benefit would require many thousands of patients, due to a relatively low absolute risk. Studies of such a large size appear unlikely ever to occur, as the BRIDGE study itself was quite ambitious and took almost a decade to complete. The inclusion of certain high-risk patient groups in these studies (especially BRIDGE) was not sufficient to confidently exclude the possibility that some of them could still benefit from bridging – but no study has ever demonstrated such a benefit either.

Interpretation/Opinion: Reductions in thromboembolism from bridging remain theoretical, but the increased risk of bleeding is consistent across studies and clinically important. If any group

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 7 of patients would receive net benefit from bridging, their absolute risk of thromboembolism would need to be much higher than the patients represented in the studies mentioned above.

Without any firm evidence to support this estimate, it is the opinion of our subject matter expert panel that the absolute risk of thromboembolism would need to be at least fourfold higher, if not more than that, to result in a net benefit to patients, even if it were to be assumed that bridging therapy does indeed reduce the risk of thromboembolism (which has never been demonstrated). Very few patients are at sufficiently high risk for TE to meet that standard. For example, the risk of TE with aortic mechanical valves is not fourfold higher than for AF, and even mitral mechanical valves may not quite meet the fourfold standard. Our SME panel feels that there is an increasing body of evidence, and an increasing consensus, that the overwhelming majority of patients will receive net harm from bridging. Bridging should only be offered after careful consideration, and for highly selected patients. Patients should be informed that the practice of bridging is non-evidence-based. While we may fear the consequences of a thromboembolic event – and justifiably so – no study has ever shown that bridging reduces this risk, and every study that has been completed so far suggests a marked increase in bleeding from bridging. In most cases, our expert panel would advise clinicians to think very carefully before offering bridging to a patient.

PBM-CPPO-Anticoagulation SME Workgroup Warfarin Interruption Guidance – Revised December 11, 2015 8

Detailed Recommendations Note: Material that is taken from AT9, without changes, is in blue. Other material is new, and reflects changes in the evidence.

*”Bridge” Therapy refers to the parenteral, short-acting anticoagulant for warfarin patients requiring short term, temporary interruption of anticoagulation for an invasive procedure. This document is not intended to address Perioperative VTE prophylaxis.

Perioperative Anticoagulation General Points

If the bleeding risk of a planned procedure is sufficiently high, warfarin therapy may be “held”, or intentionally interrupted. However, it should be noted that interruption may not be necessary for low-risk procedures, and in many cases, the correct answer to the question of how long to “hold” warfarin is in fact, not at all. (Level A Evidence)

In addition, the clinician should remain alert to the possibility of delaying procedures, particularly if they are elective and non-urgent. This can sometimes put the patient into a lower-risk category for TE, obviating the need to consider bridging. This is especially true when a patient has experienced a thromboembolic event (arterial or venous) within the past 3 months. (Level A Evidence)

If a decision has been made to interrupt therapy, and the initial INR is therapeutic, the last dose of warfarin should be 5 (or 6) days preoperatively. Shorter or longer holding periods may be necessary for out-of-range INR values. Longer holding periods may be considered for very high-risk procedures (e.g. CNS), or for patients expected to have a slow rate of INR decline (e.g. advanced age, heart failure. (Level B Evidence)

When a decision has been made to interrupt warfarin therapy, another possible consideration is whether to “bridge” the patient using low molecular weight heparin (LMWH) during the days before and/or after the surgery, until the INR is once again therapeutic.

The practice of bridging to protect the patient against thromboembolism (TE) makes intuitive sense, but no study of it has ever demonstrated a benefit, while several studies (summarized above) have now demonstrated that most patients experience net harm from this practice. Therefore, the PBM-CPPO-Anticoagulation SME Workgroup generally recommends that bridging be used sparingly, for highly selected patients at very high risk of TE. In cases of uncertainty, the PBM-CPPO-Anticoagulation SME Workgroup generally recommends that the clinician err on the side of omitting bridge therapy. (Level A Evidence)

In particular, studies have suggested that bridging is usually not helpful for patients with atrial fibrillation and a CHADS2 score of 0-47 or for patients with venous thromboembolism (VTE) which occurred more than 12 months ago.8 Another study, still unpublished, suggests that bridge therapy does not yield an important benefit among patients with mechanical aortic…