Reversing)Warfarin) · AF: RD Lopes, J Thromb Thrombolys 2008; 26: 167 Y Miyasaka et al,...

Reversing Warfarin

Alex Gallus Webinar, 27 August 2013

Warfarin & other Oral An4coagulants

•  Atrial Fibrilla8on Life-‐long, to prevent systemic embolism (>85% cerebral)

•  DVT & PE 3 months to indefinite, to prevent extension, embolism & late recurrence

•  Mechanical Heart Valves (ONLY warfarin) Life-‐long, to prevent valve thrombosis and systemic embolism

•  Other

AF: RD Lopes, J Thromb Thrombolys 2008; 26: 167 Y Miyasaka et al, Circulation 2006; 114: 119 Australian data for VTE: Access Economics & ANZ Working Party 2008

Age-‐related Burdens of AF and VTE

Warfarin §  Absorbed quickly and fully §  Cleared slowly with t½ ≈ 36 – 42 hrs

o R-‐Warfarin 45 hrs o S-‐Warfarin 29 hrs & is the more potent

§  Preformed clobng factors cleared with t½ between 6 hrs for FVII and 60 – 72 hrs for FII

§ Warfarin effect most closely follows F II level §  INR best indicator once steady state §  Dosing changes take several days to flow through

New Oral Agents are completely different

Warfarin Apixaban, Rivaroxaban, & Dabigatran

Absorp8on Tmax 2-‐4 hrs Tmax 2-‐4 hrs

Onset of an8coagulant effect when start therapy

SLOW Delayed by clobng factor clearance (T½ from 6 hrs for FVII to 60 hrs for F II)

FAST Concentra8on dependent

An8thrombo8c 4 – 6 days un8l INR ≥ 2 Hours

Clobng Tests Predict thrombosis / bleed No clinical relevance

Dose Adjust For Target INR For CrCL, not aXa/aIIa

Loss of an8coagulant effect when stop therapy

SLOW Warfarin T½ 36 – 42 hrs, plus 8me to generate new VII, X, IX, II

FAST T½ 12 – 14 hrs, for both drug concentra8on & clobng effects

Warfarin

Target INR AF 2 – 3 DVT & PE 2 -‐ 3 Mechanical Heart Valve(s) ≥ 2.5 – 3.5 Other ?

Ischaemic Stroke, ICH & INR in AF

From ESC Guidelines for AF (Fuster V, 2006)

Reversing the Warfarin Effect

1.  Why? 2.  When? 3.  How?

An Update of Consensus Guidelines for Warfarin Reversal HA Tran et al, for ASTH. MJA 2013; 198 (4): 1-‐7.

1. Why? •  Help control bleeding •  Reduce bleeding risk

2. When? a)  Clinically important bleeding b)  No bleeding, but high INR adding

unacceptable bleeding risk -‐ depends on i.  level of INR, and ii.  intrinsic bleeding risk

c)  For major interven8ons (urgent or planned)

For clinically important bleeding a)  Hold warfarin, measure INR, give Vitamin K1 b)  Manage the bleeding site

•  Iden8fy •  Local measures •  Transfusion / Volume support

d)  Replace vitamin K dependent clobng factors •  Prothrombin Concentrate (II, IX, X, not VII) •  ± Fresh Frozen Plasma (all clobng factors)

Just Stopping Warfarin is Slow Placebo or 1 mg Oral Vitamin K, INR 6 – 12

No or Minor Bleed (n = 59) Ageno W, JACC 2005; 46: 733

Results aEer 24 hours

2.5 mg Oral Vit K is Also Slow 107 Pa8ents without Bleed & INR >10

(Crowther MA, T&H 2010; 104: 118)

24 HOURS

INR 2 -‐ 6

INR > 10

No big Difference between Oral or Intravenous Vitamin K

Any difference is small with star8ng INR 6 – 10 or >10

Oral (2.5 or 5 mg), or iv (0.5 or 1 mg) for INR 6-‐10 or >10

Lubetsky AM, Archives Internal

Medicine 2003; 163: 2469

INR 6 -‐ 10

INR > 10

Major Bleeding: Reverse warfarin AND Replace Clobng Factors II, VII, IX, X

•  Vitamin K1, 5 – 10 mg iv •  Prothrombin Complex Concentrate (PCC) (Prothrombinex-‐VF; factors II, IX, X – not VII) – Freeze-‐dried, recons8tuted to small volume, infuse 50 IU/Kg over 20 – 30 minutes

•  Fresh Frozen Plasma (Factor VII + others) – 150 – 350 mL with PCC – 15 mL/kg if no PCC – Repeat INR aver PCC/FFP and next day


If PCC, then do we need FFP? (Prothrombinex-‐VF® lacks F VII)

25 IU/kg for ‘Par8al Reversal’ No FFP (n = 15)

50 IU/kg for ‘Complete Reversal’ No FFP (n = 35)

50 Pa8ents needing rapid Warfarin effect reversal; INR before and 30 mins aver three factor PCC

H Tran et al, Internal Medicine Journal 2011; 41: 337 -‐ 43

If PCC, then also give Vitamin K Warfarin is cleared slowly, therefore PCC effect is followed by rebound of INR if no Vitamin K

Yasaka M, Thrombosis Research 2002; 108: 25 -‐ 30

Concerns about Prothrombin Concentrates

•  Thrombogenicity? – Most likely with ‘ac8vated concentrates’ – Prothrombinex®-‐VF also contains ATIII/heparin – Few reports with ‘unac8vated’ concentrates (high dose, liver failure)

•  Virus Transmission? –  Inac8vated blood product

•  TRALI? – Lacks an8-‐human leukocyte an8gen or granulocyte an8bodies

High INR without Bleeding

1.  Es8mate the risk of early bleeding This is high if

•  Major bleed within past 4 weeks •  Major surgery within past 2 weeks •  Platelet count < 50 X 109/L •  Known liver disease •  An8platelet Therapy


INR > 10 without Bleeding Cease warfarin a. High early bleeding risk

•  3 – 5 mg Vitamin K1 orally or iv •  Consider Prothrombinex-‐VF 15 – 30 IU/kg •  Measure INR 12 – 24 hrs, then daily •  Resume warfarin (reduced dose) when INR close to therapeu8c range

b. Not high early bleeding risk •  Consider omibng Prothrombinex-‐VF


INR 4.5 – 10 without bleeding

Cease warfarin a. High early bleeding risk

•  Consider 1 – 2 mg Vitamin K1 orally or 0.5 – 1 mg iv

•  Measure INR within 24 hrs •  Resume warfarin (reduced dose) when INR close to therapeu8c range

b. Not high early bleeding risk •  Consider omibng Vitamin K1


Need we reverse Warfarin if INR <10? •  Bleeding is strongly associated with high INR, but risk during next 2 -‐3 days is usually small

•  Conserva8ve management is usually safe for pa8ents without bleeding

Randomised Trial (INR 4.5 – 10, no bleeding)

Oral Vitamin K 1.25 mg (n = 355)

Placebo (n = 365)

Average d1 decrease in INR 2.8 1.4 ≥ 1 Bleeding episode to 90 d 15.8% 16.3% Major Bleeding 2.5% 1.1%

MA Crowther, Annals Internal Medicine 2009; 150: 293 -‐ 300

Vitamin K and ‘warfarin resistance’

•  High doses of Vitamin K (5 mg or more) may reduce INR below target range for some days and cause temporary resistance to warfarin

•  Consider not giving vitamin K if – No ac8ve bleeding – No high risk of early bleeding –  INR < 10


INR above target range but < 4.5, without bleeding

•  Reduce or omit next warfarin dose •  Early repeat INR •  Resume therapy once INR approaches target range

•  There is usually no need to reduce dose If INR is just above target range (up to 10%)


Warfarin & Invasive Procedures

1.  Consider procedural bleeding risk No or li{le dosing change for most dental, ophthalmic and minor skin procedures

2.  Consider risk of TE without an8coagulant a)  High: AF (CHADS2 5 – 6, recent stroke / TIA, valvular heart

disease); VTE (recent or high risk thrombophilia); Any mechanical mitral or older aor8c (ball) valve

b)  Moderate: AF (CHADS2 3 – 4); VTE (3 – 12 months or recurrent); Bileaflet aor8c valve with added risk factors

c)  Low: AF (CHADS2 0 – 2); VTE (≥ 12 months); Bileaflet aor8c valve without added risks


Warfarin and Invasive Procedures

1.  Low bleeding risk: Con8nue warfarin (consider INR 2 – 2.5)

2.  High bleeding risk / Low thrombosis risk •  Stop warfarin 4 – 5 days before procedure •  Proceed if INR < 1.5 •  Restart previous warfarin maintenance dose on evening of procedure

•  VTE prophylaxis as indicated, un8l INR > 2


3.  High bleeding risk / High thrombosis risk •  Stop warfarin 4 – 5 days before procedure •  Once INR < 2, ‘bridge’ to procedure with LMWH (last dose 24 hr before) or UFH (stop 4-‐ 6 hrs before), and proceed if INR < 1.5

•  Restart warfarin evening of procedure •  Postopera8ve LMWH or UFH (escalate dose when haemostasis permits) un8l INR >2

4.  Urgent surgery •  Correct the INR (Vit K, PCC), then proceed

Warfarin and Invasive Procedures


To prevent high INR

•  Effec8ve pa8ent educa8on •  Avoid high loading doses when star8ng warfarin (5 or 10 mg/d, preferably ≤ 5 mg/d for the elderly)

•  Consider poten8al warfarin-‐drug interac8ons •  Test INR more oven aver star8ng, stopping or changing dose of other drugs

•  Allow 8me for dose-‐adjustment to have effect •  Accept small devia8ons from target range (e.g. 1.8 – 4.0) without dose-‐adjustment


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Reversing)Warfarin) · AF: RD Lopes, J Thromb Thrombolys 2008; 26: 167 Y Miyasaka et al,...

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