D.35 PHARMACY SERVICE POLICY _ PROCEDURE NO.ADM-12 ANTICOAGULATION.pdf

DEPARTMENT OF VETERANS AFFAIRS (VA)

NORTH TEXAS HEALTH CARE SYSTEM

June 26, 2017

PHARMACY SERVICE POLICY AND PROCEDURE NO. ADM-12

ANTICOAGULATION THERAPY MANAGEMENT- PROCEDURES (ATMP)

I. PURPOSE:

To outline procedures that support or supplement VA North Texas Health Care System (VANTHCS) Memorandum No. 119-18.

II. POLICY:

ATMP is a supplementation to the VANTHCS MEMORANDUM NO 119-18.

ATMP is a clinical reference to managing anticoagulation. ATMP will serve as guidance to for prescribers, nursing, and pharmacy at VANTHCS (with or without affiliation with Anticoagulation program).

(1) High Risk, High Alert Medication Management under VANTHCS

MEMORANDUM NO. 119-07;

(2) VHA Directives 1033

(3) ISMP and Joint Commission High-Alert medication safety

(4) Applicable clinical practice guidelines

(5) Veterans Health Administration (VHA) Clinical Pharmacy Practice Office (CPPO) Pharmacy Benefits Management (PBM)

III SCOPE:

D.35 RFP: 36C25722R0015

ATMP applies to all VANTHCS facilities medical staff who prescribes and or administers medications. This includes but not limited to physicians, resident physician medical students, physician assistants, clinical pharmacists, pharmacist-residents, advance practice registered nurses, unit nurses or equivalent, and nurse trainees.

In order to avert patient harm, minimize therapeutic, and communications issues this ATMP DOES NOT apply to:

(1) non-VA prescribers, with or without affiliation with VANTHCS, who prescribe anticoagulants and follow patients independently- this is also includes providers under “Choice Program” or other programs

(2) patient enrolled in anticoagulation related research programs or on experimental anticoagulation or other pharmacotherapies

(3) traveling veterans who are managed by other VA Medical Centers

(4) veterans residing in areas not under the VANTHCS

(5) VANTHCS veteran residing in or traveling to other countries; and to

(6) any other situations as determined by the VANTHCS

Attachment A

Warfarin Dosing for Patient’s Newly Initiated on Warfarin

Initial warfarin dosing in hospitalized and outpatient patients may be individualized. May consider co-morbidies, prior dose response, or clinical judgement.

Veterans Health Administration (VHA) Clinical Pharmacy Practice Office (CPPO) Pharmacy Benefits Management (PBM) has provided strong practice recommendation on warfarin management in regards to algorithm for initiation of warfarin. An algorithm generally is for guidance and does not supersede clinical experience in initiation. The following is an excerpt of their guidance.

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.1,2

Measurement Day INR Action

Measure PT/INR on Day

Baseline INR Start patient on 2 to 5 mg depending on risk factors

Measure PT/INR on Day 3-4

<1.5

1.5-1.9

Increase weekly dose by 5-25%

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

1.5-1.9

Increase weekly dose by 10-25%

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

1.5-1.9

Increase weekly dose by 15-35%

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

1.6-1.9

Increase weekly dose by 15-35%

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

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.

References:

1. DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey LM:

Pharmacotherapy: A Pathophysiologic Approach, 2014. 8th Ed.:

www.accesspharmacy.com (Figure 26-8)

2. Rose, A. J. (2014). VHA CPPO Pharmacy Benefits Management (PBM) Strong Practice Recommended Warfarin Management Algorithm (Initiation Phase of Therapy). Washington, DC: VHA.

Attachment B

Recommended Therapeutic INR Range of Anticoagulation

Table 1: Summary of Recommendation on INR Range and Duration for Warfarin theapy1,2,3

Indication INR Goal Duration of Treatment

DVT/PE

Proximal DVT of leg provoked by nonsurgical transient risk factor

2.0 to 3.0 3 months (Grade 1B)

Isolated distal DVT of leg provoked by surgery or by nonsurgical transient risk factor

2.0 to 3.0 3 months (Grade 1B)

Unprovoked DVT of leg (distal/proximal) 2.0 to 3.0 At least 3 months and re-evaluate after three months for risk-benefit ratio of extended therapy (Grade 1B)

Second unprovoked VTE with moderate or low bleeding risk

2.0 to 3.0 Extended anticoagulant therapy

(Grade 1B for low bleeding risk)

(Grade 2B for high bleeding risk)

Provoked PE by a nonsurgical transient factor

2.0 to 3.0 3 months

Indication INR Goal Duration of Treatment and re-evaluated after three months for risk-benefit ratio of extended therapy (Grade 1B)

Unprovoked PE 2.0 to 3.0 At least 3 months and re-evaluate after three months for risk-benefit ratio of extended therapy (Grade 1B)

Indication INR Goal Duration of Treatment

CARDIAC/VASCULAR DISEASE

Electrical or Pharmacologic Cardioversion 2.0 to 3.0 At least 3 weeks prior or abbreviated with TEE/ At least 4 weeks after cardioversion (Grade 1B)

Aortic Bioprosthetic valve (in normal sinus, and with no other indication for warfarin)

Aspirin 81 mg over warfarin therapy for patients in sinus rhythm for 3 months1

2.0 to 3.0 3 months2

(Class IIa; Level of Evidence C)2

Mitral Bioprosthetic Heart valve 2.0 to 3.0 3 months (Grade 2c)1

(Class IIb; Level of Evidence B)2

Aortic Mechanical Heart Valve (with risk for thromboembolism such as AF, previous TE, LV dysfunction, or hypercoagulable condition) or older-generation of mechanical AVR like ball-in-cage)

2.5 to 3.5 Indefinite (Class I; Level of Evidence: B)

Mitral Mechanical Heart Valve1,2 2.5-3.5

Indefinite (Grade 1B)1 (Class I; Level of Evidence B)2

Mechanical Heart Valves in both aortic and mitral position1,2

2.5-3.5 Indefinite ((Grade 2C)1

Aortic Mechanical Heart Valve (without risk for thromboembolism)2

2.0 to 3.0 Indefinite (Class I; Level of Evidence: B)2

Table 2: CHEST Classification of Recommendations on Valvular Guidelines1

Grade Grade of Recommendation

1A Strong recommendation, high-quality evidence

1B Strong recommendation, moderate-quality evidence

1C Strong recommendation, low-or-very-low quality evidence

2A Weak recommendation, high-quality evidence

2B Weak recommendation, moderate-quality evidence

2C Weak recommendation, low-or very-low-quality evidence

Aortic Mechanical Heart Valve 2.0 to 3.0

Indefinite (Grade 2C))1

Aortic Mechanical Heart Valve (without risk for thromboembolism)2

2.0 to 3.0 Indefinite

(Class I; Level of Evidence: B)2

Table 2: ACC (American College of Cardiology/ American Heart Association) Classification of Recommendation and Level of Evidence

References:

1. Whitlock RP, Sun JC, Fremes SE. 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.2012; 141(2)(Suppl):e576S-e600S.

2. American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 2014 AHA/ACC Guideline for the Management of Patients with Valvular Heart Disease. JACC. 2014; 63(22):e57-185.

3. Kearon C, Akl EA, Omelas J. Antithrombotic Therapy of VTE Disease: CHEST Guideline and Expert Panel Report.

CHEST. 2016; 149(2):315-352

Attachment C

REVERSAL OF HEPARIN AND LWMH EFFECT WITH PROTAMINE SULFATE

General Protamine Dosing Guidelines:

One mg of protamine sulfate neutralizes approximately 100 units of UFH.

Maximum recommended single dose of protamine is 50mg.

Repeated dose – decrease by 1 mg for every minute of time that has elapsed since previous protamine infusion.

Timing of reversal for Intravenous UFH: check aPTT 5 – 15 minutes after protamine administration to confirm that heparin is being neutralized

Precautions:

Severe hypotension and anaphylactoid reactions can occur with rapid administration.

Patients with the following conditions are at increased risk of hypersensitivity to protamine:

1. Hypersensitivity to fish

2. Infertile or vasectomized men

3. Previous exposure to protamine (insulin that contains protamine)

Protamine Dosing for IV Heparin Overdosage1:

Time Since Last Heparin Dose (min)

Dose of Protamine (mg) to Neutralize 100 units of Heparin

<30

30 to 60

0.5 to 0.75

60 to 120

0.375 to 0.5

>120

0.25 to 0.375

When heparin is given as a continuous IV infusion, only heparin given in the preceding several hours should be considered when administering protamine. Give 1mg per 100 units of heparin infused over last 3 – 4 hours.

Low Molecular Weight Heparin

Expect incomplete reversal:

Dosing for Protamine sulfate (1% solution) for reversal for enoxaparin:

<8 hours have elapsed since last dose – give 1mg for every 1mg of enoxaparin

8 – 12 hours since last dose – give 0.5mg for every 1mg of enoxaparin>12 hours since last dose – protamine not recommended.

Dosing for Protamine sulfate (1% solution) for reversal for dalteparin:

Slow infusion of protamine sulfate at a dose of 1 mg protamine for every 100 anti-Xa IU of dalteparin given. A second infusion of 0.5mg protamine sulfate per 100 anti-Xa IU of dalteparin may be considered.

Reference

1. Packet insert for Heparin

2. Lovenox ® [package insert]. Bridgewater, NJ: Sanofi-aventis U.S. LLC; 2013

3. Fragmin ® [package insert]. New York, NY: Pfizer; 2007

Attachment D

Approaches for Management of Supratherapeutic INR Clinic

Table 1: An Approach Towards Management of Supratherapeutic INR in Anticoagulation Outpatient Clinic1

INR Is Bleeding Present?

Action

At or above Therapeutic Range

Yes - Refer patient to Emergency Department for evaluation above goal but <4.5 No No change in dose or

- Hold 1-2 doses of warfarin and/or Decrease dose by 5-10% AND

- F/U in 3-7 days

>4.5, but <10 No - Hold 1-2 doses of warfarin and check INR in 48 – 72 hours OR

- Hold 1 dose, and check INR in 24 - 72 hours OR

- Decrease warfarin dose by 5-10% and check INR in 3-7 days OR

- Refer patient to Emergency Department for evaluation

>10 but <20 No - Consider admission for observation if necessary OR

- Hold warfarin, give vitamin K 2.5-5 mg PO and recheck in 24 - 48 hours.

- Administer additional vitamin K if INR still above goal

INR Is Bleeding Present?

Action

- When INR is therapeutic, resume warfarin, but decrease dose by 10- 20%, check INR in 3 - 7 days

Phytonadione 5mg tablet will be used for 2.5-5 mg PO dose of Vitamin K

All vitamin K doses will be administered and directly observed in the clinic.

*All supratherapeutic INR with bleeding should present to Emergency Department during non-business hours of the Anticoagulation Clinic.

VHA CPPO Pharmacy Benefits Management (PBM) Strong Practice Recommended Warfarin Management Algorithm (Maintenance Phase of Therapy)2-5

Disclaimer: This algorithm is a suggestion 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.

Table 2: VHA CPPO PBM Strong Practice Recommended Warfarin Management Algorithm for Patients with 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.

3.01-3.20 Consider not changing the dose unless a consistent pattern has been observed; 1 repeat INR in 7-14 days.

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.

If there is no clear reason for the INR elevation, consider referring patient for medical evaluation.

Serious Bleeding

Regardless of INR

Hold warfarin and refer patient to emergency department immediately.

Table 3: VHA CPPO PBM Strong Practice Recommended Warfarin Management Algorithm for Patients with 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 INR in 7-14 days.

2.00-2.29 If falling or low on two or more occasions, increase weekly dose by 5-10%; repeat INR in 7-14 days.

2.30-2.49 Consider not changing the dose unless a consistent pattern has been observed;1 INR in 7-14 days.

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 repeat INR in 7-14 days.

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.

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 nonstandard 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, A. J. (2014). VHA CPPO Pharmacy Benefits Management (PBM) Strong Practice Recommended Warfarin Management Algorithm (Initiation Phase of Therapy). Washington, DC: VHA.

Attachment E

Peri-operative Management of Anticoagulation – Risk Assessment

Indication for Anticoagulant Therapy

To mitigate bleeding during a surgical procedure or thromboembolic events during the interruption of anticoagulation, one strategy is to classify bleeding and thromboembolic risks in low, moderate, or high. Multiple guidance statements have been published or awaiting publication1,2,3. However, perioperative management shall remain individualized towards the patient's risk factors for bleeding and the inherent planned bleeding risk for procedures as determined by surgeon. Some instances may necessitate use of a parenteral anticoagulant during temporal interruption of anticoagulation, or withholding anticoagulation therapy, or such strategies may not be warranted. Use of a parenteral agent as a perioperative management is considered "bridging." Bridging in low to moderate thromboembolic risk patients have been associated with increased risk of bleeding with low benefit as evident in fewer thrombosis 4,5.

Table 1: General Risk Stratification Strategy for Bleeding Risk

Risk Stratum/

Management

Mechanical Heart Valve

Atrial Fibrillation2 VTE

High

Bridge with therapeutic-dose SC LMWH or IV

UFH

Any mitral valve prosthesis

Older (caged-ball or tilting disc) aortic valve prosthesis

Recent (within 6 months) stroke or

TIA

Rheumatic valve disease (?)

CHA2DS2-VASc 7 to 9 (risk for thromboembolism >10%/year) or CHADS score ≥ 5

Or Recent (within 3 months) stroke, or

TIA, SE

Recent (within 3 months) VTE;

Severe thrombophilia (homozygous Factor V Leiden genotype, deficiency of protein C, protein S or antithrombin, APS or multiple thrombophilic abnormalities)

Risk Stratum/

Management

Mechanical Heart Valve

Atrial Fibrillation2 VTE

Moderate

If increased risk of bleeding, interruption of VKA without bridging is recommended.

May bridge or not.

But many experts prefer not to bridge.

Decision should consider bleeding risk of surgery and bleeding profile of patient.5

Bileaflet aortic valve prosthesis and one of the following:

Atrial fibrillation, prior stroke or TIA, HTN, DM, CHF, age >75 yr.

CHA2DS2-VASc score of 5 to 6 (risk for thromboembolism 5% to 10%/year), or CHADS score > 3-4 or history of prior ischemic stroke, TIA, or peripheral arterial embolism (3 or months previously)

VTE within the past 3-12 months;

Non-severe thrombophilia

(heterozygous Factor V Leiden or Prothrombin gene mutation)

Recurrent VTE;

Active Cancer (treatment within 6months or palliative care)

Low

No bridging or

Low-dose

SC LMWH

Bileaflet aortic valve prosthesis

Without atrial fibrillation and no other risk factor for stroke

CHA2DS2-VASc score of ≤4 (risk for thromboembolism <5%/year) or CHADS score 0-2 or no prior history of ischemic stroke, TIA, or SE, Single VTE occurred >12 months ago and no other risk factors

CHA2DS2-VASc scoring system is as following:

Congestive heart Failure (1 point)

Hypertension (1 point)

Age (≥ 75 years) (2 points)

Diabetes (1 point)

Stroke or transient ischemic attack (TIA) or thromboembolism (2 points)

Vascular disease (1 point)

Age (64-74 years) (1 point)

Sex category is female (1 point).

CHA2DS2 scoring system is as following:

Congestive heart Failure (1 point)

Hypertension (1 point)

Age (> 75 years) (1 point)

Diabetes (1 point)

Stroke or transient ischemic attack (TIA) or thromboembolism (2 points)

General Guidelines of Peri-procedural Anticoagulation Management

Bleeding Risk

Thromboembolic Risk

High Moderate Low

High Before procedure:

Stop warfarin 5 days before.

Bridge with full dose SC LMWH or IV UFH 2 – 3 days before procedure.

Last dose of LMWH 24 hours before procedure.

After procedure:

Resume warfarin after 12-24 hours or when hemostasis has been achieved.

Bridge with LMWH or IV UFH starting 48-72 hours after procedure

Before procedure:

Stop warfarin 5 days before.

Bridge with full dose SC LMWH starting 2-3 days before procedure.

Last dose of LMWH 24 hours before procedure.

Resume warfarin after 12-24 hours or when hemostasis has been achieved.

Bridge with LMWH starting 48-72 hours after procedure

Before procedure:

Stop warfarin 5 days before.

Resume warfarin 12-24 hours after or when hemostasis has been achieved.

Low Before procedure:

Continue uninterrupted warfarin prescription (keep INR in therapeutic range).

Continue warfarin

Before procedure:

Continue uninterrupted warfarin, or stop warfarin 5 days before surgery and bridge with LMWH starting 2-3 days before procedure. Last dose of LMWH 24 hours before procedure.

Before procedure:

Continue uninterrupted warfarin, or stop warfarin 5 days before procedure.

No bridging.

After procedure, resume warfarin

Bleeding Risk

Thromboembolic Risk

After procedure:

Continue warfarin if not interrupted.

Resume warfarin 12-24 hours after procedure if interrupted.

May resume LMWH 24 hours after procedure after 12-24 hours if stopped before procedure.

Anticoagulation therapy in the setting of neuraxial anesthesia increases the risk for spinal or epidural hematoma which may result in paralysis. Although black box warning exists for anticoagulants, manufacturers stray from distinguishing specific instructions on avoidance of sequela as result of neuraxial anesthesia. The American Society of Regional Anesthesia and European Society of Regional Anesthesia and Pain Therapy published guidance on strategies for interruption and resumption of anticoagulation therapy. (refer to Table 3). Their guidelines recommend discontinuing dabigatran 4 to 5 days prior or 6 days in patients with end stage renal disease; discontinuing rivaroxaban or apixaban 3 to 5 days prior, and reinitiating DOACs 24 hours post procedure.

Table 3: Recommended Time Intervals Before and After Neuraxial Puncture or Catheter Removal6

Time before puncture/ catheter manipulation or removal

Time after puncture/catheter manipulation or removal

Unfractionated heparin (prophylaxis dosing)

4 to 6 h 1 h

Unfractionated heparin (for treatment) i.v. 4 to 6 h sc 8 to 12 h

1 h

LMWH (for prophylaxis) 12 h 4 h

LMWH (for treatment) 24 h 4 h

Fondaparinux (for prophylaxis, 2.5 mg per day)

36 to 42 h 6 to 12 h

Rivaroxaban (for prophylaxis)

22 to 26 h 4 to 6 h

Apixaban (for prophylaxis) 26 to 30 h 4 to 6 h

Dabigatran Refer to Package insert 6 h

Warfarin INR ≤ 1.4 After catheter removal

Argatroban 4 h (longer if patient has hepatic insufficiency)

2 h

Information limited for edoxaban. Above is only general recommendations provided by citation.

References:

1. Kearon Clive, Akli EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease:

CHEST Guideline and Expert Panel Report. Chest. 2016; 149(2):315-352.

2. Doherty JU, Gluckman TJ, Hucker WJ, et al. 2017 ACC Expert Consensus Decision Pathway for Periprocedural Management of Anticoagulation in Patients with Nonvalvular Atrial Fibrillation. JACC. 2017.

3. Duoketis JD, Sypropoulous AC, Spencer FA, et al. Antithromboembotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines in Perioperative Management of Antithrombotic Therapy.

CHEST. 2012; 141(2) (Suppl):e326S-e350S.

4. Duoketis JD, Spyroulous AC, Kaatz S, et al. Perioperative Bridging Anticoagulation in Patients with Atrial fibrillation. N Engl J Med 2015. Aug 2015; 373:823-833.

5. Clark NP, Witt DM, Davies LE, et al. Bleeding, Recurrent Venous Thromboembolism, and Mortality Risks During Warfarin Interruption for Invasive Procedures. JAMA.

2015;175(7):1163-1168.

6. Gogartern W, Vandermeulen E, Aken HV, et al. Regional Anaesthesia and Antithrombotic Agents: Recommendation of European Society of Anesthesiology. Eur J Anaesthesiol 2010;27:999-1015.

Attachment F

Table 1: Perioperative interruption of direct oral anticoagulants: a suggested management approach

Patient renal function Low bleeding risk surgery

(2 or 3 drug half-lives between last dose and surgery)¥

High bleeding risk surgery

(4 or 5 drug half-lives between last dose and surgery)€

Dabigatran (150 mg twice daily)

Normal or mild impairment

(CrCl >50 mL/min)

Last dose: 2 days before surgery (skip 2 doses)

Last dose: 3 days before surgery (skip 4 doses)

Moderate impairment

(CrCl 30-50 mL/min)

Last dose: 3 days before surgery Last dose: 4-5 days before surgery(skip 6-8 doses)

Rivaroxaban (20 mg once daily)

Normal or mild impairment

(CrCl >50 mL/min)

Last dose: 2 days before surgery (skip 1 dose)

Last dose: 3 days before surgery (skip 2 doses)

Moderate impairment

(CrCl 30-50 mL/min)

Last dose: 2 days before surgery (skip 1 dose)

Last dose: 3 days before surgery (skip 2 doses)

Severe renal impairment*

(CrCl 15-29.9 mL/min)

Last dose: 3 days before surgery

(skip 2 doses)

Last dose: 4 days before surgery (skip 3 doses)

Apixaban (5 mg twice daily)

Normal or mild impairment

(CrCl > 50 mL/min)

Last dose: 2 days before surgery

(skip 2 doses)

Last dose: 3 days before surgery (skip 4 doses)

Moderate impairment

(CrCl 30-50 mL/min)

Last dose: 3 days before surgery (skip 4 doses)

Last dose: 4 days before surgery

(skip 6 doses)

¥ Aiming for mild to moderate residual anticoagulant effect at surgery (<12%-25%) €Aiming for no or minimal residual anticoagulant effect (<3-6%) at surgery *Patients receiving rivaroxaban, 15 mg once daily

There is limited guidance with edoxaban in perioperative management. Manufacturer package insert for edoxaban suggests discontinuing edoxaban 24 hours prior to surgical procedure. Onset of edoxaban (1-2) hours may be considered in the decision making on resumption of edoxaban once hemostasis has been achieved2.

1. Spyropoulos AC, Douketis JD. How I treat anticoagulated patients undergoing an elective procedure or surgery.

Blood. 2012;120(15):2954-62.

2. Savaysa® [package insert]. Parsippany, NJ. Daiichi Sankyo, Inc. 2015.

Attachment G

Estimated Bleeding Risk of Some Surgical Procedures5

Low bleeding risk (<1.5%) High bleeding risk (1.5% or higher)

Dental

Tooth extraction, root canal

Dermatology:

Minor skin procedures (excision of basal cell carcinoma, actinic keratosis, nevi, and premalignant lesions)

Extensive excision of malignant melanoma

Cardiovascular

Pacemaker and defibrillator placement; EP Studies

Cardiac Surgery

Vascular surgery

Gastro-intestinal

Gastrointestional (GI) endoscopy including mucosal biopsies GI colonoscopy if associated with large polypectomy (>1cm)

Endoscopic Retrograde Cholangiopancretomy (ERCP) without sphincterotomy.

ERCP with sphincterotomy

Liver biopsy

Low bleeding risk (<1.5%) High bleeding risk (1.5% or higher)

Interventional Radiology

Venous access Tansvenous ablation or arterial puncture

Simple catheter exchange in well-formed nonvascular tracts (e.g., gastrotomy, nephrostomy tubes)

Tunneled dialysis catheters

Thoracocentesis Chest tube placement

Paracentesis Percutaneous transhepatic cholangiography or nephrostomy

Aspiration of easily accessible abdominal or pelvic abscess

Neurology & Neurosurgery

Spinal and epidural anesthesia

Lumbar puncture

Intracranial and spinal surgery

Ophthalmology

Cataract Posterior chamber surgery

Retrobulbar anesthesia (controversial)

Low bleeding risk (<1.5%) High bleeding risk (1.5% or higher)

Orthopedic surgeries

Arthrocentesis Arthroscopic surgery

Joint replacement

Pulmonary

Diagnostic bronchoscopy with or without BAL Transbronchial biopsy Tumor ablation

Reference:

1. Duoketis JD, Spyropoulos AC, Spencer FA, et al. Perioperative Management of Antiththrombotic Therapy:

Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. CHEST.2012; 141(2) (Suppl):e326S-e350S.

Attachment H

GUIDELINES FOR MONITORING FULL INTENSITY LMWH THERAPY/

FONDAPARINUX

Low Molecular Weight Heparin (LMWH), such as dalteparin (Fragmin) or enoxaparin (Lovenox), is the preferred long term anticoagulant for patients whom developed a venous thromboembolism in the setting of cancer.1 Fondaparinux (Arixtra), a pentasaccharide factor Xa inhibitor, may be considered in those patients at increased concern for heparin induced thrombocytopenia (HIT). Renal insufficiency has the potential to cause drug accumulation with both LMWH and fondaparinux.

Dosing of LMWH

Will be based on packet insert or recent literature2,3 Patient weight:

Weight should be documented in CPRS to allow dose calculation In the event of significant weight changes, dose should be adjusted, unless weight changes due to volume status shift, in which case measuring anti-Xa level to assess current drug level may be advisable. Patients should be informed to contact prescriber or anticoagulation clinic of significant weight change such as weight gain or loss greater than 10 lbs.

Dalteparin recommended dosing in patients with cancer and symptomatic venous thromboembolism is 200 IU/kg total body weight for the first 30 days of treatment, then starting on month 2 dosing is 150 IU/kg.4 Refer to table 3

Rounding doses of enxoxaparin or fondaparinux:

Rounding is usually performed to the nearest marking on syringes as described in tables 1,2, and 3.

Rounding to the nearest syringe for enoxaparin may be deemed safer for patient whose vision is limited or due to dexterity concerns.

Table 1 Rounding Dosing for Patients on Enoxaparin (1 mg/kg Q12H) or Fondaparinux with Creatinine Clearance > 30mL/min

Patient Weight (kg) Enoxaparin Twice Daily Dosing

(1 mg/kg Q12H)

Fondaparinux

Once Daily

40-44 Enoxaparin 40mg Q12H Fondaparinux 5mg Q24H

45-54 Enoxaparin 50mg Q12H Fondaparinux 5mg Q24H

55-64 Enoxaparin 60mg Q12H Fondaparinux 7.5mg Q24H

65-74 Enoxaparin 70mg Q12H Fondaparinux 7.5mg Q24H

75-84 Enoxaparin 80mg Q12H Fondaparinux 7.5mg Q24H

85-94 Enoxaparin 90mg Q12H Fondaparinux 7.5mg Q24H

95-104 Enoxaparin 100mg Q12H Fondaparinux 10mg Q24H

105-114 Enoxaparin 105mg Q12H Fondaparinux 10mg Q24H

115-127 Enoxaparin 120mg Q12H Fondaparinux 10mg Q24H

128-142 Enoxaparin 135mg Q12H Fondaparinux 10mg Q24H

143-155kg Enoxaparin 150mg Q12H Fondaparinux 10mg Q24H

Table 2 Rounding Dosing for Patients on Enoxaparin Once daily Dosing with Creatinine Clearance > 30mL/min

Patient Weight

(kg)

Enoxaparin Twice Daily Dosing

(1.5 mg/kg Q24H)

40-43 Enoxaparin 60mg Q24H

44-49 Enoxaparin 70mg Q24H

50-56 Enoxaparin 80mg Q24H

57-63 Enoxaparin 90mg Q24H

64-73 Enoxaparin 100mg Q24H

74-84 Enoxaparin 120mg Q24H

85-94 Enoxaparin 135mg Q24H

95-104 Enoxaparin 150mg Q24H

>104 Consider Fondaparinux 10mg Q24h

Table 3 Dose of Dalteparin for treatment of VTE in Patients with Cancer4

Body Weight (kg) Dalteparin (IU) (prefilled syringe) once daily for

First 30 days

Dalteparin (IU) (prefilled syringe) once daily starting on Month 2

≤ 56 10,000 7,500

57 to 68 12,500 10,000

69 to 82 15,000 12,500

83 to 98 18,000 15,000

≥ 99 18,000* 18,000

*May consider enoxaparin 1 mg/kg SUBQ Q12H to prevent underdosing

Dialysis Patients: Enoxaparin has not been FDA approved for use in dialysis patients.

There is no specific dosing information from the manufacturer regarding dialysis patients. Route of elimination is primarily renal excretion and serious bleeding complications have been reported in patients on dialysis treated with enoxaparin.

Enoxaparin use should be avoided in patients on dialysis due to lack of safety data.

Fondaparinux is contraindicated in patients with creatinine clearance (CrCl) <30ml/min and in dialysis patients.5

Monitoring effect of anticoagulation for LMWH

Monitoring is not required for most patients.

Consider monitoring for patients with the following conditions:

o Impaired renal function (< CrCl 50 ml/min),3,7 o Body weight < 50 kg, o Morbid obesity (> 150kg)6,7 o Recurrent thrombosis despite LMWH therapy o If LMWH dose has been rounded to the nearest syringe resulting in significant (>10%) over- or under-dosing relative to body weight.

o Pregnancy

Monitoring is achieved with anti-Xa levels specific for the anticoagulant Target peak levels are correlated with clinical effect which are drawn 4 hours after subcutaneous injection.8 Anti-Xa levels generally drawn after steady state is reached (after the 3rd to 4th dose)

Table 4 Peak Plasma Anti-Factor Xa levels for LMWH and Fondaparinux in Adults8,9

Table 5 Dosing Nomogram for Treatment Doses of Enoxaparin10,11

Peak Anti-Xa level (U/mL)

Hold next dose

Dosage change

Next anti-Xa level

<0.35 NO Increase 25% 4 hours after next dose

0.35-0.49 NO Increase 10% 4 hours after next dose

0.5-1.0 NO NO Next day, then within 1 week

1.1-1.5 NO Decrease 20% Before next dose

1.6-2.0 For 3 hours Decrease 30% Before next dose and 4 hours after next dose

>2.0 Until anti-Xa <0.5 U/mL

Decrease 40% Before next dose and q12h until anti-Xa <0.5 U/mL

Drug Timing of anti-Xa peak level

Therapeutic anti-Xa peak level (U/mL)

Enoxaparin Draw 4 h after injection Once-daily dosing: 1.0 to 2.0

Twice-daily dosing: 0.6 to 1.0

Dalteparin Draw 4 h after injection 1.05

Fondaparinux Draw 3 h after injection 1.20 to 1.26

Occasionally, monitoring of Anti-Xa trough levels may be used to evaluate accumulation in patients with severe renal impairment. Levels should be taken prior to the next dose after steady state has been achieved. . Desired trough anti- Xa level for enoxaparin is 0.5U/mL.7

Frequency of Long term monitoring of LMWH

Laboratory monitoring of LMWH includes but not limited to reviewing serum creatinine, H/H, platelets, and weight every 3-6 months or as clinically indicated.

Anti-Xa monitoring may be indicated as mentioned later.

Primary care provider and or other appropriate specialty provider directly involved with patient’s anticoagulation will be notified via progress note or verbal communication regarding concern for risk/benefit of continuation of LMWH in their patients.

Patient will be referred to emergency department if patient is experiencing signs and symptoms or laboratory findings concerning for bleeding or thrombosis.

Fondaparinux Monitoring Guidelines

Dosing based on packet insert5 (table 1) Long term monitoring of fondaparinux includes but not limited to reviewing serum creatinine, H/H, platelets, and weight every 3-6 months or as clinically indicated Primary care provider and or other appropriate specialty provider directly involved with patient’s anticoagulation will be notified via progress note or verbal communication regarding concern for risk/benefit of continuation of fondaparinux in their patients.

Patient will be referred to emergency department if patient is experiencing signs and symptoms or laboratory findings concerning for bleeding or thrombosis.

Monitoring for heparin-induced thrombocytopenia (HIT) for LMWH in the inpatient setting

Obtain baseline CBC with platelets and serum creatinine Obtain a platelet count daily for 3 days, then at least every 3rd day while on

LMWH. For post-surgery patients, get platelet count at least every other day for post-op days 4-14 or until LMWH is stopped.

A decline in the platelet count to < 150,000/microliter or of more than 50% from baseline value even if nadir remains greater than 150,000/microliter should prompt clinical and laboratory investigation for HIT.12,13

Monitoring for heparin-induced thrombocytopenia (HIT) for LMWH in the outpatient setting

Although monitoring of platelet counts facilitate the recognition of HIT, it is difficult to perform in the outpatient setting. However, monitoring should be considered when the risk of HIT is relatively high (>1%) such as those who undergone major surgery, specifically cardiac surgery.12,13

If suspected, the patient should be referred for emergency medical care for further evaluation, as management requires both discontinuation of low molecular-weight heparin (and any other forms of heparin) and administration of an alternative anticoagulant such as a direct thrombin inhibitor.

Venny Wong, PharmD, CACP Clinical Pharmacy Specialist, North Texas HealthCare System

Ishak Mansi, MD VA staff internist, North Texas HealthCare System Professor of Medicine and Clinical Science, University of Texas Southwestern, Dallas, TX

Date: March 30, 2017

1. Lee AYY, Levine MN, Baker RI, et al. Low-Molecular-Weight Heparin versus a Coumarin for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer. New England Journal of Medicine. 2003;349(2):146-153.

2. Lovenox. [package instert]: Bridgewater, NJ: Sanofi-Aventis U.S. LLC; 2013.

3. DeCarolis DD, Thorson JG, Clairmont MA, Leuthner AM, Rector TS, Johnson

GJ. Enoxaparin outcomes in patients with moderate renal impairment. Archives of Internal Medicine. 2012;172(22):1713-1718.

4. Fragmin. [package insert]: New York, NY: Pfizer, Inc.; 2016.

5. Arixtra. [package insert]: Research Triangle Park, NC.: GlaxoSmithKline; 2009.

6. Patel JP, Roberts LN, Arya R. Anticoagulating obese patients in the modern era.

British Journal of Haematology. 2011;155(2):137-149.

7. Nutescu EA, Spinier SA, Wittkowsky A, Dager WE. Low-Molecular-Weight

Heparins in Renal Impairment and Obesity: Available Evidence and Clinical Practice Recommendations Across Medical and Surgical Settings. Annals of Pharmacotherapy. 2009;43(6):1064-1083.

8. Nutescu EA, Burnett A, Fanikos J, Spinler S, Wittkowsky A. Pharmacology of anticoagulants used in the treatment of venous thromboembolism. Journal of Thrombosis and Thrombolysis. 2016;41(1):15-31.

9. Babin JL, Traylor KL, Witt DM. Laboratory Monitoring of Low-Molecular-Weight

Heparin and Fondaparinux. Semin Thromb Hemost. 2016(EFirst).

10. Monagle P, Michelson AD, Bovill E, Andrew M. Antithrombotic Therapy in

Children. Chest. 2001;119(1, Supplement):344S-370S.

11. Gulseth, M. 2007. Managing Anticoagulation Patients in the Hospital. Bethesda, MD: American Society of Health-System Pharmacists.

12. Linkins L-A, Dans AL, Moores LK, et al. Treatment and Prevention of Heparin-

Induced Thrombocytopenia: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141(2, Supplement):e495S-e530S.

13. Greinacher A. Heparin-Induced Thrombocytopenia. New England Journal of Medicine. 2015;373(3):252-261.

Attachment I

Table 3. Overview of US-Labeled Guidance for DOAC Anticoagulant Transitions1

DOAC Warfarin Intravenous

Anticoagulant LMWH/Other DOAC

Apixaban2 Apixaban→warfarin:

Discontinue apixaban and begin a parenteral anticoagulant and warfarin at the time the next scheduled apixaban dose would have been taken

Apixaban→parenteral anticoagulant:

Discontinue apixaban and begin the new anticoagulant at the usual time of the next dose of apixaban

Apixaban→LMWH/oth er DOAC:

Discontinue apixaban and begin the LMWH/other DOAC at the usual time of the next dose of apixaban

Warfarin→apixaban:

Discontinue warfarin and start apixaban when INR <2.0

LMWH/other DOAC→apixaban:

Discontinue current DOAC/LMWH and begin apixaban at the usual time of the next dose of the other

DOAC/LMWH

Dabigatran3 Dabigatran→warfarin

For CrCl ≥50 mL/min, start warfarin 3 days before discontinuing dabigatran

For CrCl 30–50 mL/min, start warfarin

2 days before discontinuing dabigatran

Dabigatran→parenteral anticoagulant:

Wait 12 h (CrCl ≥30 mL/min) or 24 h (CrCl<30 mL/min) after last dabigatran dose before initiating a parenteral anticoagulant

Dabigatran→LMWH:

Wait 12 h (CrCl >30mL/min) or 24 h (CrCl <30 mL/min) after last dabigatran dose before initiating a parenteral anticoagulant

For CrCl 15–30 mL/min, start warfarin 1 day before discontinuing dabigatran

Warfarin→dabigatran

Discontinue warfarin and start dabigatran when INR <2.0

UFH→dabigatran:

Start dabigatran at the time of continuous infusion discontinuation

LMWH→dabigatran:

Start dabigatran 0–2h before the time that the next LMWH dose would have been given

Edoxaban4 Edoxaban →warfarin:

Oral option: Reduce daily edoxaban dose by 50% and begin taking warfarin concomitantly.

Measure INR at least weekly just before edoxaban dose. Once a stable INR > 2.0 is achieved, discontinue edoxaban and continue warfarin

Parenteral option:

Discontinue edoxaban and administer a parenteral anticoagulant and warfarin at the time of the next scheduled edoxaban dose.

Edoxaban→parenteral anticoagulant:

Discontinue edoxaban and start the parenteral anticoagulant at the time of the next scheduled dose of edoxaban

Edoxaban→LMWH/ other DOAC:

Discontinue edoxaban and start the LMWH/other DOAC at the time of the next scheduled dose of edoxaban

Warfarin→edoxaban:

Discontinue warfarin and start edoxaban when the INR is <2.5

UFH→ edoxaban:

Discontinue UFH infusion and start edoxaban 4 h later

LMWH/other DOAC→edoxaban:

Discontinue current DOAC/LMWH and start edoxaban at the time of the next scheduled other DOAC/LMWH dose

Rivaroxaban5 Rivaroxaban→warfarin

Discontinue rivaroxaban and begin a parenteral anticoagulant and initiate warfarin at the time the next scheduled rivaroxaban dose would have been taken

Rivaroxaban→UFH:

Discontinue rivaroxaban and initiate the parenteral anticoagulant at the time the next rivaroxaban dose would have been taken

Rivaroxaban→LMWH/ other DOAC:

Discontinue rivaroxaban and start the LMWH/other DOAC at the time of the next scheduled dose of rivaroxaban

Warfarin→rivaroxaban:

Discontinue warfarin and start rivaroxaban as soon as INR <3.0

UFH→rivaroxaban:

Stop UFH infusion and administer rivaroxaban at the same time

LMWH/other DOAC→rivaroxaban:

Start rivaroxaban 0–2 h before the next scheduled evening LMWH/other DOAC dose and omit administration of the LMWH/other DOAC

Reference:

1. Raval AN, Cigarroa JE, Chung MK, et al. Management of patients on non-vitamin k antagonist oral anticoagulants in the acute care and periprocedural setting: a scientific statement from the American Heart Association. Circulation. 2017;135:00.

doi:10.1161/CIR.00000000000004772. Eliquis ® [package insert]. Princeton, NJ:

Bristol-Myers Squibb Company and Pfzier Inc; 2016.

3. Pradaxa ® [package insert]. Ridgefield, CT: Boehringer Ingelheim Pharmaceuticals, Inc; 2015.

4. Savaysa ® [package insert]. Parsippany, NJ: Daiichi Sankyo Co., LTD; 2015.

5. Xarelto ® [package insert]. Titusville, NJ: Janseen Pharmaceuticals, Inc.; 2016.

Appendix

4F-PCC 4 factor Prothrombin Complex Concentrate

ACS Acute coronary syndrome (ACS)

ACS Acute coronary syndrome

AF Atrial fibrillation

APLS Antiphospholipid Syndrome

APTT

Activated Partial Thromboplastin Time

(APTT)

ATPC Anticoagulant Therapy Program Coordinator

ATPM Anticoagulation Therapy Program Manager

CPRS computerized patient record

CPS Clinical Pharmacy Specialist

DOACs Direct Oral Anticoagulants (DOACs)

DTIs Direct Thrombin Inhibitors

DVT Deep vein thrombosis

ERCP

Endoscopic Retrograde Cholangiopancretomy

HBPC Home Based Primary Care

HIT Heparin Induced Thrombocytopenia

INR International Normalized Ratio

LMWH Low Molecular Weight Heparin (LMWH):

MI Myocardial infarction

P&T Pharmacy and Therapeutics

PCP primary care provider

PE Pulmonary embolism

QA Quality assurance

SE Systemic embolism

TEE Transesophageal echocardiography

UH unfractionated heparin

VANTHCS VA North Texas Health Care System

VTE Venous thromboembolism