What evidence supports giving vitamin K to a patient with elevated INR associated with alcoholic cirrhosis?

Comment by InpharmD Researcher

Despite the scarcity of evidence supporting the use of vitamin K in reducing elevated INR likely induced by cirrhosis, the 2019 American Gastroenterological Association (AGA) clinical update recommends 10 mg PO or intravenous (IV) vitamin K in cirrhotic patients with potential vitamin K deficiency. Without a standardized dosing protocol, responsiveness to the first-dose vitamin K may be used as a clinical indicator for subsequent doses. Evidence primarily limited to retrospective reviews observed variations in dosing regimen and routes of administration, with IV 10 mg vitamin K for three days being proposed most frequently. Regardless, administration of vitamin K led to conflicting results in INR reduction and clinical outcomes. As most literature did not categorize cirrhosis by etiologies, further elaboration on optimal dosing regimens specifically for alcoholic cirrhosis can not be made.

Background

According to the 2019 American Gastroenterological Association (AGA) clinical update for managing coagulation in cirrhotic patients, vitamin K supplementation may be considered, either as a 10-mg tablet PO or 10-mg intravenously (IV), in patients who experienced prolonged antibiotic therapy, poor nutrition, or severe malabsorption. However, the clinical benefits of vitamin K in hospitalized patients with cirrhosis remained uncertain, as limited data provide guidance on optimal routes of administration, dosing regimen, and specific patient population. In general, if patients achieve inadequate response to the first dose of vitamin K, the possibility of therapeutic effects with repeated doses is likely low. [1]

A recent review also noted a lack of standardized protocol for vitamin K in cirrhotic patients who are not on warfarin due to minimal, conflicting evidence (see Tables 1-5). The majority of the studies are retrospective in nature, with variations in dosing regimen, routes of administration, and study population (acute liver failure vs. chronic cirrhosis). Additionally, a 2019 case series of 5 patients also revealed variable and unpredictable effects of vitamin K (one to three doses of 10 mg PO or IV). Despite its frequent use in practice, literature reported minimal effects of vitamin K on reducing the surrogate marker, INR. Given the possible adverse events (e.g., hypersensitivity reactions and increased thrombosis) associated with IV administration, routine use should be evaluated with caution. However, with potential benefits in vitamin K deficiency, the authors suggested IV vitamin K should be carefully considered in critically ill cirrhotic patients or those with active bleeding to assist in correcting underlying vitamin K deficiencies. Similar to the guideline recommendations, responsiveness to a single dose of vitamin K may be used to guide subsequent administrations. Typically, PO vitamin K should be avoided due to decreased absorption commonly observed in cirrhotic patients. Compared to subcutaneous and intramuscular administration, IV exhibited a more predictable pharmacokinetic profile and a better safety profile, respectively. [2], [3]

Lastly, a 2011 paper mentioned that vitamin K deficiency is seen in decompensated liver cirrhosis secondary to various complex mechanisms. The authors recommend 10 mg of vitamin K injections for three days, as it is adequate enough to correct the vitamin K deficiency. There is no mention of the effects of this correction on INR, however, they do highlight that vitamin K may not be useful if the patient has no deficiency. [4]

References: [1] O'Leary JG, Greenberg CS, Patton HM, Caldwell SH. AGA Clinical Practice Update: Coagulation in Cirrhosis. Gastroenterology. 2019;157(1):34-43.e1. doi:10.1053/j.gastro.2019.03.070
[2] Jin S, Hong L, FakhriRavari A. The Role of Vitamin K in Cirrhosis: Do Pharmaco-K-Netics Matter? Gastrointestinal Disorders. 2022;4(1):15-21. doi:10.3390/gidisord4010003
[3] Aldrich SM, Regal RE. Routine Use of Vitamin K in the Treatment of Cirrhosis-Related Coagulopathy: Is it A-O-K? Maybe Not, We Say. P T. 2019;44(3):131-136.
[4] Amarapurkar PD, Amarapurkar DN. Management of coagulopathy in patients with decompensated liver cirrhosis. Int J Hepatol. 2011;2011:695470.
Literature Review

A search of the published medical literature revealed 5 studies investigating the researchable question:

What evidence supports giving vitamin K to a patient with elevated INR associated with alcoholic cirrhosis?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→


Please see Tables 1-5 for your response.

Select studies evaluating the use of vitamin K 
Study/Design Population Intervention Limitations Conclusion

Alperin et al., 1987

Retrospective cohort, multicenter

N= 42
Critically ill patients, 17 to
78 years old with a vitamin K deficiency (prolonged PTs)—36% with abnormal liver function tests

20–25 mg IV vitamin K once followed by 5 mg three times a week PO or IV
  • Various doses of vitamin K
  • Deficiency not solely attributed to cirrhosis (all received at least 2 antibiotics, renal insufficiency, and inadequate diet)

All patients with a diagnosed vitamin K deficiency exhibited a response to therapy 4–6 h after infusion and complete correction of coagulopathy within 12 h

Pereira et al., 2005

Prospective randomized, double-blind, single-center

N = 49
Patients 16 to 73 years old with or at high risk of developing acute liver failure

10 mg IV vitamin K vs. 10 mg PO vitamin K vs. placebo
  • Assessed acute liver failure (76% with acetaminophen hepatotoxicity)
  • Mean INR on admission of 6.4

Minority of patients with severe acute liver dysfunction have a subclinical vitamin K deficiency; this is corrected by a single dose of IV vitamin K. While 94% of patients receiving IV vitamin K had increased serum vitamin K, only 20% who received PO had increased serum vitamin K. 

Saja et al., 2012

Prospective cohort, multicenter

N = 128
Adult patients (mean age
49 years) recruited into 4 groups: inactive hepatitis B (n = 23), chronic viral hepatitis B or C (n = 21), cirrhosis (n = 24), or hepatocellular carcinoma (n = 21)

Vitamin K 10 mg SQ once (n = 89) vs. no vitamin K administration (n = 39 healthy individuals, mean age 38 years)
  • Vitamin K-dependent factors were only measured twice (baseline and at 72 h)
  • Vitamin K administered SQ instead of IV
  • Baseline confounding

SQ vitamin K in patients with advanced liver dysfunction resulted in very minimal, likely clinically insignificant improvement in PT only (no improvement of FVII, protein C or S) in cirrhosis group. 

Recommendations based on pharmacokinetics of varying vitamin K formulations
Route PO IV Subcutaneous Intramuscular 
Black boxed warning None

Fatal hypersensitivity reactions

 None Fatal hypersensitivity reactions
Adverse effects  Diaphoresis, cyanosis, dizziness, flushing, hypotension, tachycardia

Hematoma formation, diaphoresis, cyanosis, dizziness, flushing, hypotension, tachycardia
Absorption  Unlikely in advanced liver disease Readily Variable Readily
Time to ↓ INR 6 to 10 h (peak 24 to 48 h) 1 to 2 h (peak 12 to 24 h) Variable (peak at 72 h) Variable

Recommendation for cirrhosis-associated coagulopathy

 Consider avoiding use Consider in actively bleeding or critically ill patients with vitamin K deficiency Consider avoiding use

Should be avoided
References:
[1] Adapted from:
[2] Jin S, Hong L, FakhriRavari A. The Role of Vitamin K in Cirrhosis: Do Pharmaco-K-Netics Matter? Gastrointestinal Disorders. 2022;4(1):15-21. doi:10.3390/gidisord4010003

 

Appropriateness of Using Vitamin K for the Correction of INR Elevation Secondary to Hepatic Disease in Critically ill Patients: An Observational Study

Design

Retrospective cohort study 

N= 98

Objective

To evaluate the efficacy and safety of vitamin K in the correction of international normalized ratio (INR) elevation secondary to liver disease in critically ill patients 

Study Groups

Vitamin K (n= 47)

No vitamin K (n= 51)

Inclusion Criteria

Age ≥18 years, critically ill, hepatic disease and significant INR elevation (INR ≥1.5) within 24 h of ICU admission

Exclusion Criteria

Prolonged antibacterial therapy for ≥21 days, prior administration of any oral anticoagulant, receiving prothrombin complex concentrate (PCC) or fresh frozen plasma (FFP) simultaneously with vitamin K, comorbidities that cause coagulopathy other than hepatic diseases or that increase bleeding/thrombosis risk

Methods

Electronic medical records were retrospectively reviewed to identify eligible patients based on vitamin K administration during their ICU stay at a tertiary-care academic referral hospital in Saudi Arabia. For bleeding outcomes, major bleeding was defined as clinically overt bleeding associated with a Hgb fall ≥20 g/L, transfusion of ≥2 U packed red blood cells (PRBC) or whole blood, retroperitoneal or intracranial bleeding, or requiring urgent medical intervention. Minor bleeding included events not fulfilling the criteria of major or clinically significant bleeding. 

Duration

Between January 1st, 2018, and December 31st, 2018

Follow-up: until insensitive care unit (ICU) discharge or in-hospital death

Outcome Measures

Primary: incidence of bleeding

Secondary: degree of INR correction, incidence of thrombosis, transfusion requirement, mechanical ventilation duration, ICU length of stay (LOS), and 30-day mortality

Baseline Characteristics

  

Vitamin K (n= 47)

No vitamin K (n= 51)

 p-value

Age, years

 63.5  58.2 Not significant (NS) 

Female

44.7% 45.1% NS 

Body mass index (BMI), kg/m2

 29.1 27.1 NS

Comorbidities 

Hypertension

Diabetes mellitus 

Chronic kidney disease 

 

46.8%

59.6%

23.4%

 

37.3%

31.4%

9.8%

 

< 0.0001

< 0.0001

< 0.0001

Previous antibiotics within 3 months of ICU admission

 48.9% 19.6% 0.0021

Laboratory parameters 

INR

Activated partial thromboplastin time (aPTT)

Platelet count

Total bilirubin 

 

2.2

51.0

14.5

94

 

1.5

51.5

4.5

19.1

 

< 0.0001

NS

0.0164

< 0.0001

ICU scores 

APACHE II

SOFA

 

22.0

11.0

 

17.0

7.0

 

0.0056

0.0001

Vitamin K was given by IV route of administration to 93.6% of the patients, with a median dose of 10 mg and for a median duration of three days. 

Results

Endpoint

Vitamin K (n= 47)

No vitamin K (n= 51)

Odds ratio (95% confidence interval [CI])

Patients with bleeding out of those without bleeding at the time of treatment

Major 

Minor

 

3/27 (11.1%)

0 

 

1/51 (2.0%)

0

 

2.4 (0.28 to 21.67)

-

Thrombosis (all cases)

 9 (19.2%) 6 (11.8%) 1.2 (0.32 to 4.85)

30-day mortality

 29 (61.7%) 7 (13.7%) 2.7 (0.79 to 9.01)
      Beta coefficient (Estimates) (95% CI)

Transfusions, U 

RBC

Platelet

 

5.3  ± 4.62

14.5 ± 21.69

 

4.2 ± 9.41

4.5 ± 7.75

 

-0.12 (-0.76 to 0.51)

0.36 (-0.71 to 1.43)

ICU LOS (interquatile range [IQR])

 10.0 (4 to 18) 4.0 (2 to 10) 0.67 (0.22 to 1.12); p= 0.003

Mechanical ventilation duration, days 

 3.0 (1.00 to 8.00) 0.0(0.00 to 2.50) 0.93 (0.23 to 1.62); p= 0.01
  Vitamin K (n= 47) p-value 
Comparison of INR change Pre Post 

At dose 1

At dose 2

At dose 3 

At dose 4 

2.64

2.09

2.19

2.83

2.01

1.98

2.21

2.47

< 0.0001

0.28

0.54

0.67

Adverse Events

 See results 

Study Author Conclusions

The administration of vitamin K for INR correction in critically ill patients with coagulopathy secondary to liver disease was not associated with a lower odds of new bleeding events. Further studies are needed to assess the value of vitamin K administration in critically ill patients with liver disease-related coagulopathy.

InpharmD Researcher Critique

This study is limited by its retrospective nature and small sample size, leading to decreased power to detect statistically significant differences in outcomes of interest. Additionally, unadjusted variations in ICU populations (medical vs. surgical) and secondary liver diseases may further confound the study outcomes. 



References:
[1] Al Sulaiman K, Al Mutairi M, Al Harbi O, et al. Appropriateness of Using Vitamin K for the Correction of INR Elevation Secondary to Hepatic Disease in Critically ill Patients: An Observational Study. Clin Appl Thromb Hemost. 2021;27:10760296211050923. doi:10.1177/10760296211050923

 

The effectiveness of intravenous vitamin K in correcting cirrhosis-associated coagulopathy

Design

Retrospective, single-cohort review

N= 96

Objective

To evaluate the effectiveness of intravenous (IV) vitamin K in cirrhosis

Study Groups

Cirrhotic patients (n= 96)

Inclusion Criteria

Diagnosed cirrhosis, at least one administration of IV phytonadione, baseline INR > 1.5, at least one repeat INR 6-14 hours after administration

Exclusion Criteria

 Concurrent use of therapeutic anticoagulation, acute liver failure, missing data

Methods

This was a retrospective review of patients who were admitted to a single institution in the US. The effectiveness of IV vitamin K was defined as a 30% decrease in INR or a reduction in INR to an absolute value of ≤ 1.5. 

Duration

From September 2013 to July 2014

Outcome Measures

Primary: effectiveness of IV vitamin K

Baseline Characteristics

  

Cirrhosis (n= 96)

Age, years

 54

Male

 85 (88.5%)

Weight, kg

 86

Child-Pugh Class C

 85 (88.5%)

INR

 3.0

Results

Endpoint

Cirrhosis (n= 96)

10% reduction in INR

 13 (13.5%)

20% reduction in INR

 10 (10.4%)

30% reduction in INR

 7 (7.3%)

40% reduction in INR

 4 (4.2%)

50% reduction in INR

 2 (2.1%)

Sixty patients did not receive an adequate response with vitamin K.

Adverse Events

Not disclosed

Study Author Conclusions

The results of this study demonstrate that the use of IV vitamin K to correct coagulopathy of cirrhosis may not be beneficial. Patients with higher degrees of INR elevation are more likely to have an effective response.

InpharmD Researcher Critique

 Non-standard times in repeating INR is a huge limitation of this retrospective study. As the study was conducted among patients with severe cirrhosis, results may not be readily applicable to cirrhotic patients with different disease severities. 



References:
[1] Rivosecchi RM, Kane-gill SL, Garavaglia J, Maclasco A, Johnson H. The effectiveness of intravenous vitamin K in correcting cirrhosis-associated coagulopathy. Int J Pharm Pract. 2017;25(6):463-465.

 

Impact of Vitamin K Administration on INR Changes and Bleeding Events Among Patients With Cirrhosis

Design

Retrospective, matched-cohort review

N= 276

Objective

 To determine the effect of vitamin K administration on the INR and bleeding events among hospitalized patients with cirrhosis

Study Groups

Vitamin K (n= 130)

No vitamin K (n= 146)

Inclusion Criteria

Age > 18 years, diagnosis of cirrhosis by ICD9 code, vitamin K administration (as long as the indication was not for warfarin reversal), vitamin K started within the first four days of admission

Exclusion Criteria

 Warfarin use, transferred from an outside medical institution, incomplete data

Methods

This was a retrospective review of patients admitted to a single center in the midwest United States. Patients who were given vitamin K were matched to patients who did not receive vitamin K based on age, baseline INR, baseline SCr, and ICU care within the first seven days of hospitalization.

Duration

Between January 2010 and August 2012

Outcome Measures

 Decrease in INR, bleeding risk

Baseline Characteristics

  

Vitamin K (n= 130)

No vitamin K (n= 146)

  

Age, years

 53.3 55.5  

Male

 81 (62.3%) 95 (65.1%)  

Baseline INR

 1.95 1.66  

Baseline INR > 1.6

 82 (63.1%) 59 (40.4%)  

Route of administration

Intravenous 

Oral

Subcutaneous

Combination of these routes 

 

17 (13.1%)

47 (36%)

22 (16.9%)

44 (33.8%) 

 -  

Vitamin K dose (interquartile range [IQR])

Single dose provided, mg 

Dose over 4 days, mg

 

5 (1 to 30)

15 (1 to 50)

 -  

One patient received 90 mg over the first 7 days of hospitalization. 

Results

Endpoint

Vitamin K (n=130)

No vitamin K (n=146)

p-value 

INR decrease within 72 hours

 60 (46.2%) 48 (32.9%) 0.03

Bleeding event

 6 (4.6%) 1 (0.7%) 0.05

Of the patients who did have a decrease in INR, the mean decrease was 0.2, with 19% of the responders having a drop greater than 0.5 and 10% having a drop greater than 1.

Based on a multivariable analysis, vitamin K administration did not affect INR change (adjusted odds ratio [aOR] 1.17, 95% confidence interval [CI] 0.66 to 2.08, p= 0.59).

Adverse Events

Vitamin K had no significant impact on bleeding when analyzed in a multivariate fashion (aOR = 4.90, 95% CI 0.56 to 43.0, p=0.15). 

Study Author Conclusions

Among this cohort of patients with cirrhosis, vitamin K administration did not have a positive impact on INR changes or bleeding events. Until the relative safety of this intervention is studied, the routine use of vitamin K should be discouraged among patients with cirrhosis.

InpharmD Researcher Critique

Besides the inherent limitations of a retrospective review, the study had a small sample size that may not be generalizable to an outside population.

 

References:
[1] Meyer AV, Green M, Pautler HM, Korenblat K, Deal EN, Thoelke MS. Impact of Vitamin K Administration on INR Changes and Bleeding Events Among Patients With Cirrhosis. Ann Pharmacother. 2016;50(2):113-7.

 

Effect of Vitamin K on Coagulopathy of Liver Disease: A Single Center Retrospective Review

Design

Retrospective chart review

N= 333

Objective

To evaluate the effect of vitamin K on the INR 24-72 hours after administration

Study Groups

Study cohort (n= 333)

Inclusion Criteria

Coded diagnosis of cirrhosis, acute hepatitis, non-alcoholic steatohepatitis, hepatocellular carcinoma, or end-stage liver disease, received vitamin K

Exclusion Criteria

 Received heparin, LMWH, FFP, or if they did not have an INR value before the administration of vitamin K or 24-72 hours after the dose was given

Methods

This was a retrospective chart review from the VA Informatics and Computing Infrastructure (VINCI) database of patients who received vitamin K during the study period. Medication routes and dosing were collected from the pharmacy administration record. 

Duration 

Between January 2001 and March 2014

Outcome Measures

 INR reduction

Baseline Characteristics

  

Study cohort (n= 333)

INR on admission, mean (range)

1.88 (0.86-5.99)

Results

Endpoint

Study cohort (n=333)

Mean decrease in INR after vitamin K*

 0.08

Mean decrease in vitamin K after a second reading (n= 180)

 0.123

INR decrease >0.4

 24 (7.2%)

*95% confidence interval 0.028 to 0.132

Adverse Events

Not disclosed

Study Author Conclusions

While a statistically significant decrease in INR of 0.08 was found, it is unclear if such a difference from vitamin K would be clinically significant.

InpharmD Researcher Critique

This study did not report the baseline characteristics of the patients evaluated. The retrospective nature of the study also makes it hard to focus on clinical outcomes such as bleeding events. 



References:
[1] Hambley BC, Diamond A, Connie S, et al. Effect of Vitamin K on Coagulopathy of Liver Disease: A Single Center Retrospective Review. Blood. 2016:128(22):2583.