Anticoagulant Reversal

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2015 MICNP Conference

3/14/2015

Speaker: Matthew Bondi, PharmD

1 Anticoagulant Reversal

Matthew Bondi Pharm.D., BCPS March 14, 2015

No Conflicts of Interest to Report

Matthew Bondi Pharm.D., BCPS. Clinical Pharmacist Sparrow Hospital [email protected] Ph. 517.364.2031

Objectives

» To review guidelines for reversal of anticoagulation with or without bleeding. » To describe the various agents available for assisting in anticoagulation therapy reversal » To illustrate the use of anticoagulation reversal guidelines through a patient case

54 y/o female with Elevated INR on Admission

» HPI MM is a 85 kg, 58yo female with h/o Lupus, Rheumatoid Arthritis, Osteoarthritis, Mixed Connective Tissues Disease, h/o CVA, h/o L DVT s/p L BKA, Fibromyalgia, Hypertension, and IBS who comes as a transfer from another Hospital for septic shock. » She initially went to ED late evening on 7/23/13 for severe constant abdominal pain which occurred about 4 hours after ingestion of Bratwurst Sausage. She also had some nausea and vomiting x2 as well. » Her labs at the other hospital showed: » ALP 259, AST 85, ALT 45, Total Bili 1.4, Albumin 4.2, Creatinine 1.3, BUN 22, Hgb 13.6, Troponin 0.012, INR 9.12, aPTT 52.7, » WBC 13.9, U/A with many bacteria with large amt Leukocyte Esterase and Positive Nitrite.

54 y/o female with Elevated INR on Admission

» She was started on IV ceftriaxone and her BP continued to drop to SBP in 70s » She was transferred to Sparrow ICU for further management. » In examination, she complains of abdominal pain and diffuse joint pain from her arthritis as well. She denies any pain with urination, however does have some lower abdominal pain as well. She appears to be drowsy and her BP is in 50‐60s despite levophed 30mcg. » Pharmacy was contacted for anticoagulation reversal » Patient needs central line and arterial line.

Reversal of What?

» Unfractionated Heparin

» LMWH

» Warfarin

» Direct Thrombin Inhibitors

» Factor Xa Inhibitors

» Antiplatelet agents

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Why Reverse?

» Emergent Reversal vs. Periprocedural

» Bleeding vs. non‐bleeding

» High INR vs. Low INR

» Heparin vs. LMWH vs. VKA vs. Target

Directed

Choice of Reversal Strategy

»Pharmacology of the agent

»Clinical urgency

»Severity of bleeding

Comparison of Select Reversal Agents

Anticoagulation Therapy: A Point‐of‐Care Guide edited by William E. Dager, Michael P. Gulseth, Edith A. Nutescu

Heparin and LMWH

» Heparin and Low Molecular Weight Heparins (LMWH) (i.e. enoxaparin (Lovenox®) » Indications » DVT/PE » Afib » ACS » Warfarin bridge

Protamine for Heparin Reversal

» Mechanism » Anticoagulant when given w/o heparin » Forms a stable complex with heparin neutralizing anticoagulant effects of both » Dosing » 1 mg protamine neutralizes 100 units of heparin » Max single dose: 50 mg »Infusions: count amount given in preceding 2‐2.5 hours »Reduce dose as elapsed time since heparin given increases %0

Protamine for LMWH Reversal

»Can’t fully reverse »Excessive protamine doses may worsen bleeding »Reduce dose as elapsed time since LMWH given increases » Enoxaparin (Lovenox®) reversal »< 8 hours 1 mg protamine = 1 mg enoxaparin »> 8 hours 0.5 mg protamine = 1 mg enoxaparin

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Administration of Protamine

» Inject slowly; further dilution unnecessary » Max of 50 mg over 10 minutes » Repeat aptt 5‐15 minutes after dose, redose prn » Too rapid administration » Hypotension » Anaphylactic reactions » Heparin neutralization in 5 mins » May be diluted in D5W or NS

Oral Anticoagulants

Procoagulant

Factors

Procoagulant

Factors

Fresh Frozen Plasma Fresh Frozen Plasma Cryoprecipitate Cryoprecipitate Prothrombin Complex Concentrate Prothrombin Complex Concentrate Activated Prothrombin Complex Concentrate Activated Prothrombin Complex Concentrate rFVIIa rFVIIa

Fresh Frozen Plasma

» Obtained from human blood » Contains all the clotting factors » Dosing based on weight » Expressed as the volume or # of units of the product. » 10‐20 mL/kg Æ 20 ‐30 % increase in plasma levels of clotting factors.

Fresh Frozen Plasma

» Clinical practice: 2 units commonly prescribed. » Could be inadequate for patients with larger body weight » 200‐250mL per unit » Potentially large fluid volume »Can be beneficial in patient with volume loss »Could be problematic in patient with fluid overload.

Fresh Frozen Plasma

» Disadvantages » Need for thawing: delays administration » Large fluid volume » Potential (although low) risk of transmission of infectious disease » Transfusion reactions » Takes longer to work than other options

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2015 MICNP Conference

3/14/2015

Speaker: Matthew Bondi, PharmD

4 Prothrombin Complex Concentrates

» Concentrated pooled plasma products » Contain 3 or 4 factors » Activated versus not activated » Also may contain Proteins C,S and Z » Regulate the effects of coagulation factors » In some cases have heparin and antithrombin

Prothrombin Complex Concentrates

» 3‐factor PCCs » Bebulin® » Profilnine SD® » Factors II,IX, and X » Still contains factor VII but insignificant » Activation required via the coagulation cascade.

3‐Factor PCC: Bebulin

® » Part of Rapid Reversal Protocol » INR > 20 or serious bleeding » Life‐threatening bleeding regardless of INR » Concomitant use of FFP and Vit K » Dosing of PCC is currently a recommendation of 30 units/kg

Prothrombin Complex Concentrate

» The concentrations of the clotting factors in the products varies depending on manufacture and lot » Doses are always expressed in units of the factor IX component. » Round to nearest vial size available

Comparison of PCCs to FFP

» Correct the INR more rapidly than FFP » Prep time for PCCs is shorter » Higher concentration of clotting factors » Thrombotic events possible with PCCs

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» Effectiveness of PCC for rapid reversal of INR in patients with AAICH » Used a 3‐Factor PCCÆ Profilnine » Retrospective analysis of 19 patients with AAICH Jan 2005 through May 2006 » Compared » patients treated with FFP + Vit K » Patients treated with PCC + FFP + Vit K » Mean INR on admission for both groups » Time to reach the mean target INR for both groups » # of patient at Target INR in 3‐4 hours. » Reported death, and thrombotic complications » Treatment Protocol for FFP Group » Hold all Anticoagulants » Vit K 10mg IV » FFP 10‐15 ml/kg » INR checked at presentation » INR checked at completion of therapy » 2‐3 hours after initiation of therapy » FFP repeated if required » Serial INRs obtained at 2‐3 hours until target INR » Treatment Protocol for PCC Group » Hold all anticoagulants » Vit K 10 mg IV » Profilnine (PCC) » 25 units/kg IVP INR < 4 » 50 units/kg IVP INR >4 » Further doses after INR check 3 hours after initial dose. » FFP given same as FFP group » INR checked at presentation » INR checked at completion of therapy (Profilnine) » 1‐2 hours after initiation of therapy » Serial INRs obtained at 2‐3 hours until target INR » Results » No difference in initial INR between groups » Significant reduction in INR was observed in both groups after respective therapy » FFP + Vit K » 1.84 ± 0.31 to a mean value 1.34 ± 0.08 (p<0.05) » PCC + FFP + VitK » 2.44 ± 1.48 to a mean value 1.34 ± 0.07 (p<0.005) » Results » 3 patients in FFP group (33%) and 8 in the PCC group (80%) reached their target INR in 3‐4 hours after initiation of therapy (p=0.012) » Time to reach INR of 1.4 or less (p < 0.05) » FFP group = 8.52 ± 5.6 h » PCC group = 4.25 ± 2.12 h

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2015 MICNP Conference

3/14/2015

Speaker: Matthew Bondi, PharmD

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» Conclusions » PCC is effective in rapidly reversing the effects of anticoagulation both in terms of absolute time required and the rate of correction of INR. » The use of PCC in combination with FFP and Vit K results in decreased time required for correction of coagulopathy in emergency situations compared to FFP and Vit K alone.

4‐Factor PCCs

» Factors II, IX, X and VII

» Activation required via the coagulation

cascade

» Available in Europe and Canada for several

years

» Available in US since spring 2014.

4‐Factor PCCs

» Lack of studies comparing activity of 3 factor

PCCs to 4 factor PCCs

» Lack of studies evaluating clinical outcomes of

the PCCs.

» Thrombotic complications

» VTE, DIC, microvascular thrombosis » MI

3 vs. 4 Factor PCC products

• Included 18 Studies representing 654

patients

– ICH, Urgent Surgery, Invasive procedure or GI Bleeding

– No RCCT; No direct comparisons – Typically Elderly Patients

• Baseline INRs

– 3PCC : 3.3 to 5.1

– 4PCC : 2.3 – greater than 20

• INR within 1 hour of PCC administration

– 3PCC: 1.2 to 1.9 – 4PCC: 1 to 1.9

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• INR < 1.5 within 1 hour after PCC administration – 3PCC: 6 of 9 Study groups (67%)

– 4PCC: 12 of 13 Study groups (92%)

• Conclusions

– 4 factor PCCs are more effective than 3 factor PCCs in decreasing the INR to < within one hour of administration

• Limitations

– No direct comparisons of 3 factor PCC vs. 4 factor PCC

– A surrogate outcome (INR reversal to < 1.5 in one hour) to compare effectiveness in lieu of clinical outcomes

Factor Xa Inhibitors

» Available products » Eliquis (apixaban) » Xarelto (rivaroxaban) » Indications » DVT/PE (treat & prevent) » Nonvalvular Afib » Dose adjusted for renal insufficiency » Administration of rivaroxaban » Administer doses > 15 mg with food » May be crushed and mixed in apple sauce

Oral Direct Thrombin Inhibitor

» Available products » Pradaxa (Dabigatran) » Indications » DVT/PE (treat) » Nonvalvular Afib » Adjust for renal insufficiency » Administration » Take with or without food » Do not break capsules » Dyspepsia common

Reversal of Target Specific Oral

Anticoagulants for Life‐threatening Bleeding

No specific antidote for reversing rivaroxaban, apixaban, or dabigatran. • No available data supporting the use of FFP, rFVIIa (Novo‐Seven®), or 3‐Factor PCC (Bebulin®) in humans for reversal of the TSOACs • RBCs and other supportive care as needed • Dabigatran IS removed by hemodialysis (60% of the drug removed over 2‐3 hrs) • Rivaroxaban and apixaban ARE NOT removed by hemodialysis. • 4F‐PCC (Kcentra®) has not been studied in patients < 18 years

Non‐life Threatening Bleeding

» Delay next dose or discontinue the anticoagulant » Symptomatic treatment » Fluid replacement and hemodynamic support as needed » Blood product transfusion as needed

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2015 MICNP Conference

3/14/2015

Speaker: Matthew Bondi, PharmD

8 Warfarin (Coumadin)

» Inhibits Vitamin K dependent clotting factors (Factors II, VII, IX, X as well as Proteins C and S) » Indications » DVT/PE » Afib » Heart valves » INR monitoring » Drug and dietary interactions » Teratogenic » Delayed and unpredictable effects

Reversal of Warfarin

Without Significant Bleeding

*_{Doses have been rounded to comply with commercially available Vitamin K} 1 dosage forms.

Reversal of Warfarin

With Significant Bleeding

*Doses have been rounded to comply with commercially available Vitamin K1 dosage forms. **Vitamin K1for infusion should be mixed in D5W 50 ml and given over 30 minutes.

Reversal of Warfarin for

Surgical Procedure

54 y/o female with Elevated INR on Admission

» HPI MM is a 85 kg, 58yo female with h/o Lupus, Rheumatoid Arthritis, Osteoarthritis, Mixed Connective Tissues Disease, h/o CVA, h/o L DVT s/p L BKA, Fibromyalgia, Hypertension, and IBS who comes as a transfer from another Hospital for septic shock. » She initially went to ED late evening on 7/23/13 for severe constant abdominal pain which occurred about 4 hours after ingestion of Bratwurst Sausage. She also had some nausea and vomiting x2 as well. » Her labs at the other hospital showed: » ALP 259, AST 85, ALT 45, Total Bili 1.4, Albumin 4.2, Creatinine 1.3, BUN 22, Hgb 13.6, Troponin 0.012, INR 9.12, aPTT 52.7, » WBC 13.9, U/A with many bacteria with large amt Leukocyte Esterase and Positive Nitrite.

54 y/o female with Elevated INR on Admission

» She was started on IV ceftriaxone and her BP continued to drop to SBP in 70s » She was transferred to Sparrow ICU for further management. » In examination, she complains of abdominal pain and diffuse joint pain from her arthritis as well. She denies any pain with urination, however does have some lower abdominal pain as well. She appears to be drowsy and her BP is in 50‐60s despite levophed 30mcg. » Patient needs central line and arterial line.

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54 y/o female with Elevated INR on Admission

» Give Vitamin K 5‐10mg IVPB x1 » INR >6 » Kcentra 50 units/kg (max 5000 units) »4250 units (85 kg female) »Dose rounded to nearest vials » Check INR ½ to 1 hour after Kcentra infused, then every 12 hours x2. » Could give FFP if INR remains elevated.

Trauma Patients

» If receiving warfarin at home and INR < 1.5 » Reversal not indicated » Recheck INR in 24 h » Treatment recommendations differ based on whether the patient has evidence of either: » Head trauma » CT positive for bleed

Trauma Patients

» Patient w/o head trauma/CT negative for bleed » INR < 3: reversal not indicated » INR > 3 »But < 10 & not symptomatic: reversal not indicated »INR > 10 & not symptomatic: Vitamin K 2.5‐5 mg PO »INR > 3 & symptomatic: Vitamin K 10 mg PO or IV » Hold warfarin and recheck INR in 12 or 24 hours

Trauma Patients

» Patient with head trauma or CT positive for bleed » Hold warfarin » Vitamin K 10 mg IVPB » Administer 4F‐PCC (Kcentra) » If INR > 1.5 thirty min after Kcentra » Give FFP 2‐4 units » Recheck INR in 30 minutes » Recheck INR q 6 h X 24 h, redose vitamin K prn

Trauma Patients

» Factor Xa Inhibitors (rivaroxaban, apixaban) » When was the last dose taken »Greater than 24 hours (rivaroxaban) (renal function) »Greater than 12 hours (apixaban) » Kcentra 50 units/kg (max 5000units) » Vitamin K administration: Not necessary

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2015 MICNP Conference

3/14/2015

Speaker: Matthew Bondi, PharmD

10 Trauma Patients

» Direct Thrombin Inhibitors (dabigatran) » When was the last dose taken »Greater than 12 hours (renal function) » Feiba (activated PCC) 25 – 50 units/kg x1 »May repeat; Max 200 units/kg/day » 3 & 4 PCCs appear ineffective » Dabigatran is dialyzable (approx 60%)

Administration of Vitamin K

» Recommended routes » Oral »Tablets or injection diluted in juice »Onset: 6‐10 hours; Peak: 24‐48 hours » Intravenous (IV) »Diluted in 50 ml D5W given over 30 min. »Onset: 1‐2 hours; Peak: 12‐14 hours » Avoid SubQ or IM administration

Administration of Kcentra

» Must also give vitamin K in warfarin patients » Administer via separate IV line » Administration rate is 0.12 ml/kg/min (≈ 3 units/kg/min) up to 8.4 ml/min (≈ 210 units/min) » Repeat INR 30 minutes after 4F‐PCC then every 12 hours X 2, daily X 3‐5 days » No repeat doses » If INR does not correct consider 2‐4 units FFP

Activated PCC (Feiba®)

» Contains Factors II, VII, IX and X » Factor VII is activated. » Concern for thrombotic events. » Dosing: 500 – 1000 units » Infusion NTE 2 units/kg/min

Administration of Feiba

» Must be brought to room temperature prior to reconstitution » Administer via separate IV line » Maximum infusion rate is 2 units/kg/minute » Decrease infusion rate if HA, flushing, changes in BP/HR » Infusion must be completed within 3 hours of reconstitution

Questions?

Matthew Bondi Pharm.D., BCPS. Clinical Pharmacist Sparrow Hospital [email protected] Ph. 517.364.2031

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