hot topics in anticoagulation deborah zeitlin, pharm.d

Hot Topics In Anticoagulation

Deborah Zeitlin, Pharm.D.Assistant Professor of Pharmacy Practice

Butler University College of Pharmacy and Health Sciences

Clinical Pharmacist Specialist, Clarian Health

Disclosure Statement

This individual has the following to disclose concerning possible financial or personal relationships with commercial entities that may be referenced in this presentation.– Deborah Zeitlin, Pharm.D.: Roche

2

Objectives

• Discuss guidelines on bridging patients with heparin

• Describe current guidelines for vitamin K• Define appropriate dosing

recommendations for use of low molecular weight heparin (LMWH) with obesity and renal insufficiency

3

LM is scheduled for a root canal. What should be recommended

regarding LM’s warfarin therapy?

A. Continue warfarin therapyB. Stop warfarin 5 days prior to procedureC. Stop warfarin 5 days prior and bridge with

low molecular weight heparin therapy

D. Stop warfarin one day priorE. Check INR and confirm result is < 1.5

4

Decision Tree For Bridging

Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44. 5

Surgery/Procedure Risk Factors

•Determine anticoagulation diagnosis

•Mechanical heart valve•Atrial fibrillation•Thromboembolism

•Risks for thromboembolism

•Type of surgery•Bleeding risk•Risk of thromboembolism•Time off anticoagulation

Risk of thromboembolism versus bleedingPreference of physician and patient

Need for bridging therapy

Patient Risk Factors

Risk Of Thromboembolism

6

Thromboembolism Risk

Mechanical Heart Valve

Atrial Fibrillation Venous Thromboembolism

High •Mitral mechanical valve•Older aortic valve•Stroke or TIA in last 6 months

•CHADS2 score 5-6•Stroke or TIA in last 3 months•Rheumatic valvular heart disease

•Venous thromboembolism (VTE) in last 3 months•Severe thrombophilia

Moderate Bileaflet aortic valve & atrial fibrillation, prior TIA /stroke, diabetes, hypertension, heart failure, > 75 years

CHADS2 score 3-4 •VTE in last 3-12 months•Recurrent VTE•Nonsevere thrombophilia•Active cancer

Low Bileaflet aortic valves without atrial fibrillation and no risks of stroke

CHADS2 score 0-2(no history of stroke or transient ischemic attack (TIA))

Single VTE within past 12 months and no other risk factors

Douketis JD, et al. Chest. 2008;133:S299-S339.

Thrombophilia Classifications

Severe• Protein C deficiency• Protein S deficiency• Antithrombin

deficiency• Antiphospholipid

syndrome• Multiple thrombophilia

Nonsevere• Heterozygous Factor

V Leiden mutation• Heterozygous Factor

II mutation

7Douketis JD, et al. Chest. 2008;133:S299-S339.

CHADS2 Score

• Assess annual stroke risk in atrial fibrillation patients

• Score range: 0 – 6• One point for each factor

– Congestive heart failure (recent)

– Hypertension– Age > 75– Diabetes

• Two points: history of stroke or TIA

CHADS2 Score Stroke Adjusted Rate per 100 Patient-Years

0 1.9

1 2.8

2 4

3 5.9

4 8.5

5 12.5

6 18.2

Gage BF, et al. JAMA. 2001;285:2864-2870. 8

Warfarin Perioperative Recommendations

• For temporary interruption of warfarin requiring normal INR, stop warfarin 5 days prior to surgery/procedure (1B)

• Resume warfarin 12 to 24 hours after surgery/ procedure when adequate hemostasis exists (1C)

• May administer 1-2mg of oral vitamin K to normalize INR if INR is > 1.5 1-2 days prior to surgery/procedure (2C)


Treatment Based On Risk

10

Risk of Developing Thromboembolism

Treatment Based on Risk Strength of Recommendation

High Bridge anticoagulation with therapeutic -dose SC LMWH or IV UFH

SC LMWH preferred versus IV UFH

1C

2C

Moderate Bridge anticoagulation with therapeutic- dose SC LMWH, therapeutic-dose IV UFH or low-dose SC LMWH

Therapeutic-dose SC LMWH preferred

2C

Low Bridge anticoagulation with low-dose SC LMWH or no bridging

2C

Douketis JD, et al. Chest. 2008;133:S299-S339.

Heparin Bridging Recommendations

• Administer last SC LMWH dose 24 hours prior to surgery/procedure (1C)

• For major surgery or spinal/epidural anesthesia, only administer morning dose of LMWH if BID dosing or 50% of once daily dosing to decrease residual anticoagulant effect (1C)

• When bridging with IV UFH, stop UFH 4 hours prior to surgery

• Do not monitor anti-factor Xa levels when bridging


Restarting Heparin Bridge After Surgery/Procedure

• For minor procedures with therapeutic-dose LMWH, resume LMWH 24 hours later (1C)

• For major surgery or high risk of bleeding surgery/procedure with therapeutic-dose UFH or LMWH (1C)– Delay initiation for 48-72 hours– Use low-dose UFH or LMWH– Completely avoid UFH or LMWH

• Assess anticipated bleeding risk and hemostasis post surgery/procedure; do not resume at fixed time


Minor Surgeries & Procedures

• Dental, dermatologic, ophthalmic and gastrointestinal

• Patients usually discharged home • Patients need to be informed of expectations

– Prolonged bleeding– Major bleeding– Medical attention required

• Obtain PT/INR prior ideally 24 hours before

• Greater risk of thromboembolism than bleeding

Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44.Douketis JD, et al. Chest. 2008;133:S299-S339.

13

Dental Procedures

Continue Warfarin• Single/multiple tooth

extractions (up to 3)• Endodontics (root canal)• Dental hygiene• Restorative surgery;

supragingival• Dental scaling• Prosthetics• Crowns and bridges

Consider Other Options• Full-mouth extractions• Multiple implant

placements• Extractions of multiple

bony impactions• Gingivectomy• Orthognathic surgery

Douketis JD, et al. Chest. 2008;133:S299-S339. Jaffer AK. Cleve Clin J Med. 2009;76(4):S37-S44.

Herman WW et al. J Am Dent Assoc. 1997;128:327-335.

14

Dermatologic Surgery

• Simple excisions and Mohs surgery– Basal and squamous cell carcinomas– Actinic keratoses– Malignant or premalignant nevi– Continue warfarin therapy (1C)

• Benefits include shorter hospitalization, fewer blood tests and monitoring, and reduced cost

• Make sure INRs are within therapeutic range and stable; not greater than 4

Lam J, et al. BJPS. 2001;54(4): 372-373. Jaffer AK. Cleve Clin J Med. 2009;76 (4):S37-S44. Sugden P, et al. Surgeon. 2008;6(3):148-150.

Douketis JD, et al. Chest. 2008;133:S299-S339.Kirkorian AY, et al. Dermatol Surg. 2007;33:1189-1197.

15

Ophthalmic Procedures

• Cataract surgery, trabeculectomy• Jamula et al. showed continuing warfarin

increases bleeding risk by 3 fold in cataract surgery, but bleeding not clinically significant

• Chest only makes recommendation for cataract removal and recommends continuing warfarin (1C)

• Charles et al. states risk of ocular hemorrhage is less significant than risk of thromboembolism with intravitreal injections or intraocular surgery

Jamula E, et al. Thromb Res. 2009;124:292-299.Jaffer AK. Cleve Clin J Med. 2009;74(4):S37-S44.

Douketis et al. Chest. 2008;133:S299-S339.Charles S, et al. Retina. 2007;27(7):813-815.

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Bleeding Risk For Endoscopic Procedures

Low• Diagnostic with biopsy

– EGD, colonoscopy, flexible sigmoidoscopy

• ERCP without sphinecterotomy• Endoscopic ultrasound without

fine needle aspiration• Capsule endoscopy• Enteral stent deployment

without dilation• Enteroscopy & diagnostic

balloon-assisted enteroscopy

High• Polypectomy• Biliary/pancreatic

sphincterotomy• Pneumatic or bougie dilation• PEG placement• Endoscopic hemostasis• Treatment of varices• Cystogastrostomy• Tumor ablation• Therapeutic balloon-assisted

enteroscopy

Anderson MA, et al. Gastrointest Endosc. 2009;70(6):1060-1068. 17

Cardiac Device Surgery• Case reports demonstrate complications of

periprocedural bridging including pocket hematomas, arterial thromboembolism and increased cost– Pacemakers– Implantable cardioverter defibrillators– Cardiac resynchronization therapy

• BRUISE CONTROL trial– Bridge or continue coumadin for device surgery

randomized control trial

Birnie D, et al. Curr Opin Cardiol. 2008;24:82-87. 18

BRUISE CONTROL Trial• Randomized 1:1; moderate to high-risk patients of

arterial thromboembolism or high-risk of VTE• Primary outcome

– Clinically significant hematoma that requires reoperation and/or transfusion and/or unplanned/ prolonged hospitalization and/or interruption of LMWH, IV UFH or anticoagulation

• Secondary outcomes– Thromboembolic events, components of primary

outcomes and major perioperative bleeding

• Goal of 984 patients recruited by July 2010

Birnie D, et al. Curr Opin Cardiol. 2008;24:82-87. 19

LM is scheduled for a root canal. What should be recommended

regarding LM’s warfarin therapy?

A. Continue warfarin therapyB. Stop warfarin 5 days prior to procedureC. Stop warfarin 5 days prior and bridge with

low molecular weight heparin therapy

D. Stop warfarin one day priorE. Check INR and confirm result is < 1.5

20

RD, a 40 year old female, finished trimethoprim/ sulfamethoxazole today for a current urinary tract

infection. Her warfarin indication is Factor V Leiden Mutation, and normally her INR is 2.5 (Goal

2-3). Her INR today is 6.1 with no active bleed. What is the appropriate recommendation?

• A. Stop warfarin• B. Send to emergency room• C. Give vitamin K 5 mg orally• D. Give vitamin K 5 mg IV• E. Make no changes

21

Causes Of Nontherapeutic INRs

• Inaccurate INR testing• Changes in vitamin K intake• Changes in warfarin or vitamin K absorption• Changes in warfarin metabolism• Changes in vitamin K-dependent coagulation

factor synthesis or metabolism• Concomitant drug use• Patient noncompliance

Ansell J, et al. Chest. 2008;133:160S-198S. 22

Bleeding Risk With Elevated INR

• Absolute daily risk of bleeding is low

• Assess bleeding risk– Potential risk of

bleeding– Active bleed– INR level

• Treatment– Hold warfarin dose or

decrease– Use oral or IV vitamin K– Life-threatening bleeds

• Fresh frozen plasma• Prothrombin

complex concentrate• Recombinant factor

VIIa



Condition Intervention For Elevated INRs And Bleeding

INR <5, but more than goal

Lower or omit dose, monitor more often & restart at lower dose when INR in range; if minimally above range, no dose change needed.

INR >5 but <9, no significant bleed

Omit 1-2 doses, monitor more often & restart at lower dose when INR in range OR omit dose, give vitamin K 1-2.5mg po, if ↑ bleeding risk OR rapid reversal (urgent surgery) vitamin K < 5mg po to reduce INR within 24 hours. If INR still high, may give vitamin K 1-2.5mg po.

INR >9, no significant bleed

Hold warfarin & give vitamin K 2.5-5mg po with INR expected to decrease in 24-48 hours. Monitor more frequently. Use more vitamin K if needed. Restart warfarin at appropriate adjusted dose when INR within goal.

Serious bleed with elevated INR

Hold warfarin. Given vitamin K 10mg by slow IV infusion, supplement with FFP, PCC or rVIIa, depending upon urgency, vitamin K may be repeated at 12 hours.

Life-threatening bleed

Hold warfarin & give FFP, PCC or rVIIa supplemented with vitamin K 10mg slow IV infusion. Repeat if needed based on INR.

Administration of vitamin K

With mild to moderate elevated INR without major bleed, give vitamin K orally not subcutaneously.

Oral Vitamin K Versus Placebo

• Oral vitamin K use in over anticoagulated pts • 711 non-bleeding patients with INR 4.5 – 10

– INRs: 8.1-10 (72); 6.1-8 (185); 4.5-6 (487)

• Held 1 warfarin dose & randomized to vitamin K 1.25 mg (347) or placebo (365)

• Outcome of bleeding events within 90 days– Major (fatal, > 2 units pack red blood cells, therapeutic

intervention or confirmed bleeding in enclosed space)– Minor (medical assessment)– Trivial (no medical assessment)

Crowther MA, et al. Ann Intern Med. 2009;150:293-300. 26

Results: Oral Vitamin K Versus Placebo

• No statistical significant difference – Bleeding, thromboembolism or death

• INR decreased more rapidly with vitamin K– INR average decrease vitamin K: 2.8– INR average decrease placebo: 1.4

• Major bleeding events occurred more often in patients older than 70 years (10/13 events)

• Vitamin K safe to correct INR, prevent death & thromboembolism, but does not minimize risk of bleeding

Crowther MA, et al. Ann Intern Med. 2009;150:293-300. 27

RD, a 40 year old female, finished trimethoprim/ sulfamethoxazole today for a current urinary tract

infection. Her warfarin indication is Factor V Leiden Mutation, and normally her INR is 2.5

(Goal 2-3). Her INR today is 6.1 with no active bleed. What is the appropriate recommendation?

• A. Stop warfarin• B. Send to emergency room• C. Give vitamin K 5 mg orally• D. Give vitamin K 5 mg IV• E. Make no changes

28

Low Molecular Weight Heparin

• Benefits– Easy to use– Predictable response– Less monitoring– Less heparin induced

thrombocytopenia (HIT)– Less risk of osteoporosis

• Concerns– Less reversibility

– Accumulates in renal insufficiency

– Less experience in obesity

– Expensive

– Agents not interchangeable

Chawla LS, et al. Obes Surg. 2004;14:695-698.Hirsh J, et al. Chest. 2008;133:141S-159S.

29

Enoxaparin, Dalteparin, Tinzaparin

A 65 year old male [weight=320lbs, height=70in] with a serum creatinine of 2.8 is scheduled for hernia repair surgery. He will be bedridden for one week. What is the recommended dose of

subcutaneous enoxaparin for him for VTE prophylaxis?

• A. 30mg twice daily• B. 40mg twice daily• C. 30mg daily• D. 40mg daily• E. Avoid enoxaparin

30

Obesity And LMWH

• Maximum recommended dose in obesity– Tinzaparin and enoxaparin: none– Dalteparin 18,000 units daily (VTE treatment) & 20,000

units daily (acute coronary syndrome)– LMWH studied up to 190 kg for VTE treatment

• Treatment doses use actual body weight (2C)– Does not cause more bleeding or thromboembolic

events– BMI > 27 kg/m2: use enoxaparin 1mg/kg twice daily– Dalteparin 200 units/kg & tinzaparin 175 units/kg daily

Clark NP. Thromb Res. 2008;123:S58-S61.Hirsch J, et al. Chest. 2008;133:141S-159S.

Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

31

LMWH and VTE Prophylaxis

• A study with surgical patients demonstrated negative correlation of body weight & anti-factor Xa levels for VTE prophylaxis

• Bariatric surgery patients showed higher prophylaxis dose with less incidence of VTE and no change in bleeding risk

• Consider increasing VTE prophylactic doses by 30% with BMI > 40kg/m2

• Monitor anti-factor Xa levels in patients >190kg

Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

32

Target Anti-Factor Xa LevelsIndication LMWH Dosing Peak Range

(units/ml)Mean at 4 hrs(units/ml)

VTE Prophylaxis

Dalteparin

Enoxaparin

2500 units daily5000 units daily

30mg q 12hr40mg daily

Moderate risk: 0.01 - 0.25High risk:0.2 - 0.5

Highest risk:0.5 - 1.2

VTE Treatment

Dalteparin

Enoxaparin

Tinzaparin

1mg/kg q12hr1.5mg/kg daily

175units/kg/day

0.6 - 11 - 2

1.05

0.85

Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083. 33

Sample Enoxaparin Treatment Dosing Nomogram

Anti-Factor Xa Level (units/ml)

Hold Next Dose Dosage Change Next Anti-Xa Level

< 0.35 No ↑ 25% 4 hrs after next dose

0.35 – 0.49 No ↑ 10% 4 hrs after next dose

0.5 – 1 No None Next day, then 1 week, then monthly

1.1 – 1.5 No ↓ 20% Before next dose

1.6 – 2 3 hours ↓ 30% Before next dose and 4 hours after next dose

> 2 until anti-factor Xa <0.5units/ml

↓ 40% Before next dose & q12hr until anti-factor Xa < 0.5


Definition Of Renal Function

Description of Renal Function Glomerular Filtration Rate (ml/min)

Normal > 90

Mildly decreased 60 – 89

Moderately decreased 30 – 59

Severely decreased 15 – 29

End-stage renal disease < 15 or on dialysis


Creatinine Clearance by Cockcroft Gault Equation (ml/min)CrCl = [(140 – age)* (IBW)]/72 * SrCr (multiple by 0.85 if female)

Ideal Body WeightMale IBW: 50 kg + 2.3 kg for each inch > 5 feet

Female IBW: 45.5kg + 2.3 kg for each inch > 5 feet

Renal Insufficiency & LMWH

• If CrCl <30ml/min with therapeutic doses, use UFH instead of LMWH (2C)

• LMWH use with severe renal insufficiency and therapeutic doses, decrease dose by 50% (2C)

• More accumulation with enoxaparin than others• Watch for signs and symptoms of bleeding• Consider monitoring anti-factor Xa levels for use

>10 days if CrCl 30–60 ml/min & risk of accumulation

Hirsch J, et al. Chest. 2008;133:141S-159S.Nutescu EA, et al. Ann Pharmacother. 2009;43:1064-1083.

36

LMWH Dosing with Renal Insufficiency

Prophylaxis• 30-90ml/min: dose

adjustment not needed• CrCl <30ml/min

– Enoxaparin: 30mg daily– Dalteparin & tinzaparin

adjustment not needed if used < 10 days

Treatment• CrCl <20ml/min use

weight-based adjusted-dose IV UFH and monitor aPTT due to limited studies in LMWH

• CrCl <30ml/min – Dalteparin: use caution – Enoxaparin: 1mg/kg daily– Tinzaparin: use caution


A 65 year old male [weight=320lbs, height=70in] with a serum creatinine of 2.8 is scheduled for hernia repair surgery. He will be bedridden for one week. What is the recommended dose of

subcutaneous enoxaparin for him for VTE prophylaxis?

• A. 30mg twice daily• B. 40mg twice daily• C. 30mg daily• D. 40mg daily• E. Avoid enoxaparin

38

Hot Topics In Anticoagulation

Deborah Zeitlin, Pharm.D.Assistant Professor of Pharmacy Practice

Butler University College of Pharmacy and Health Sciences

Clinical Pharmacist Specialist, Clarian Health

hot topics in anticoagulation deborah zeitlin, pharm.d

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