Comparison PO vs. IV Vitamin K for Excessive Anticoagulation

In Review

Lubestsky A et al. "Comparison of oral vs intravenous phytonadione (vitamin K1) in patients with excessive anticoagulation: a prospective randomized controlled study". Arch Intern Med. 2003. 163(20):2469-2473.
PubMed • Full text

Clinical Question

In patients that present with a high INR associated with warfarin therapy, is IV Phytonadione (Vitamin K) superior to PO Phytonadione for returning INR to the therapeutic range of 2-4.

Bottom Line

At 24 hours, patients will reach a therapeutic INR following treatment with small dose Vitamin K, regardless if given IV or PO. IV Vitamin K will correct more quickly and has a greater chance of over-correcting and causing warfarin resistance. If the patient does not require rapid correction, PO is likely a superior treatment modality.

Almost 1/3 of the population experienced excessive anticoagulation due to a drug interaction, greater heed, closer monitoring, and a consideration of a pre-emptive dose change needs to be considered when starting new therapy with patients previously stabilized on warfarin.

Major Points

Elevated INR increases the risk of major bleeding. Treatment for high INR ranges from withholding warfarin doses to treatment with IV vitamin K. Vitamin K, while necessary for life, may pose risks including thrombosis or anaphylaxis. Various observational and comparative trials have been conducted to determine the optimal route and dosing for the bleeding and non-bleeding patient. Care is necessary as over-reversing patients with supratherapeutic INR may cause them to be warfarin-resistant and may require bridging anticoagulation until their INR returns to a therapeutic level.

The meta-analysis by DeZee et al. in 2006 suggested the IV and PO dosing was equivalent, and both were superior to subcutaneous dosing or withholding warfarin dosing.

Guidelines

2008 ACCP Antithrombotic and Thrombolytic Therapy, 8th Edition

Non-bleeding patients:

• INR <5: lower/omit a dose, monitor more frequently, resume therapy at adjusted dose when INR is therapeutic
• INR ≥5 and <9: omit one or two doses, monitor more freqently, resume at lower dose when INR is therapeutic
  • consider omitting a dose and give Vitamin K 1-2.5mg orally
  • if more rapid reversal required, consider ≤5mg Vitamin K orally
  • if not reversed at 24 hours, consider an additiona 1-2 mg Vitamin K orally
• INR >9: hold warfarin and give Vitamin K 2.5-5mg orally

Bleeding patients:

• Consider Vitamin K 10mg by slow IV, FFP, PCC, recombinant factor VIIa, depending on the situation.

2012 ACCP Antithrombotic Therapy and Prevention of Thrombosis, 9th Edition

Non-bleeding Patients:

• INR 4.5-10 suggest against the routine use of vitamin K (Grade 2B)
• INR >10.0 suggest that oral vitamin K be administered (Grade 2C)

Bleeding Patients

• rapid reversal of anticoagulation with four-factor prothrombin complex

concentrate rather than with plasma. (Grade 2C).

• Vitamin K 5-10 mg administered by slow IV injection rather

than reversal with coagulation factors alone (Grade 2C)

Design

• Single centre, Prospective, open label, observational trial
• N=61(66 episodes)
  • IV Vitamin K n=34(32)
  • PO Vitamin K n=32(29)
• Setting: not stated
• Enrollment: January 2000 to December 2001
• Mean follow-up: 28 days
• Outcomes:
  • INR Decline
  • Proportions of Patients reaching INR 2-4 at 6, 12, and 24h
• Adverse Events
  • Major bleeding Events
  • INR <2
  • Warfarin Resistance (inability to raise INR by 0.5 points)
  • thrombosis
  • other side effect

Population

Inclusion Criteria

• Treated with warfarin
• Presentation with INR ≥6.0

Exclusion Criteria

• Major bleed or urgent reversal required
• Known hypersensitivity
• Known glucose-6-phosphate dehydrogenase deficiency
• Pregnancy/Lactation
• History of thromboembolic phenomena during anticoagulation
• altered transaminases (AST/ALT 3xULN) or renal function (Serum creatinine ≥177mcmol/L [≥2.0mg/dL])
• refusal to participate

Baseline Characteristics

• No difference between IV vs. PO group for: age, weight, height, mean weekly warfarin dose
• Sex, No.(%): Men 35(57) vs. Women 26(43)
• Indication of anticoagulation, No.(%): Prosthetic Heart Valve 36(59), AFib 16(26), Pulmonary Embolism 2(3), Peripheral Vascular Disease 3(5)
• Target INR, No.(%)
  • 2.0-3.0: 22(36)
  • 2.5-3.5: 39(64)
• Mean weekly warfarin dose: Men 46.8 +/- 23.1mg vs. Women 31.2 +/- 14.3mg; P=0.002
• Cause of excessive anticoagulation, No.(%): drug interaction 18(27) [antibiotics 8(12)], Start within previous month 11(17), recent dose change 4(6), patient error 4(6), dietary change 2(3)No identifiable cause 27(41)

Presented as IV vs. PO Group

• No. of episodes(%): 35(32) vs. 32(29)
• Age, years, mean +/- SD: 64.3 +/- 14.6 vs. 60.5 +/- 16.7
• Steady State weekly Warfarin dose, mg, mean +/- SD: 36.9 +/- 16.7 vs. 42.4 +/- 24.2
• Baseline INR, mean +/- SD(Range):
  • Overall: 9.2 +/- 3.1 (62-19.4) vs. 9.1 +/- 2.7 (6.1-15.1)
  • Baseline INR 6-10: 7.6 +/- 1.0 (6.2-9.3) vs. 7.7 +/- 1.1 (6.1-9.6)
  • Baseline INR >10: 13.2 +/- 2.9 (10.7-19.4) vs. 13.0 +/- 1.7 (10.4-15.1)

Interventions

• Vitamin K dose based on presenting INR
  • PO given as tablet
  • IV diluted to 150mL with NS and infused over 30min
• INR 6-10: 0.5mg IV or 2.5mg PO
• INR >10: 1mg IV or 5mg PO

Outcomes

Comparisons are IV vs. PO; P-value

Primary Outcomes

Time to reach INR 2-4 (hours)

Baseline INR 6-10

6h: 11 vs. 0; P=0.001

12h: 16 vs. 8; P=0.03

24h: 16 vs. 20; NS

Baseline >10

6h: 1 vs. 0; NS

12h: 2 v.s 3; NS

24h: 7 vs. 6; NS

INR Response over time, INR +/- SD

4h: NR vs. 7.1 +/- 1.2

12h: 3.8 +/- 1.4 vs. 4.4 +/- 1.1

24h: 2.6 +/- 0.8 vs. 2.9 +/- 0.8

48h: 3.7 +/- 1.8 vs. 2.8 +/- 1.2

Adverse Events

Treatment Failure at 24h, INR >4

Baseline INR 6-10

1 vs. 2; NS

Baseline INR >10

3 vs. 1; NS

Anticoagulation overcorrection at 24h, INR <2

Baseline INR 6-10

7 vs. 2; NS

Baseline INR >10

0 vs. 2; NS

Warfarin Resistant INR following restart (not reaching target within 72 hrs)

0 vs. 2

Criticisms

• Non-bleeding patient cohort
• Small numbers
• No control group

Funding

Not stated