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Abstract

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography

Aim:

To evaluate the efficacy of oral menadiol compared to intravenous phytomenadione when correcting coagulopathies associated with cholestasis.

Methods:

A total of 26 patients with cholestasis and an international normalized ratio (prothrombin time) greater than 1.2, were randomized to receive either 20 mg o.d. for 3 days of oral menadiol (n=12), or 10 mg o.d. of intravenous phytomenadione (n=14) prior to endoscopic retrograde cholangeopancreatography. Liver function tests and international normalized ratio were measured daily for 3 days.

Results:

Liver function tests and international normalized ratio were comparable between groups at entry into the study (P > 0.05), but serum albumin was significantly lower in the intravenous phytomenadione group following treatment (P < 0.05). A decrease in international normalized ratio occurred in both groups following administration of vitamin K (P < 0.05). Two patients in the intravenous group required fresh frozen plasma, as failure to normalize international normalized ratio was observed. No adverse drug reactions were observed in either group, and no patient required re-admission for bleeding during a 4-week follow-up period after cholangeopancreatography.

Conclusion:

Oral menadiol appears to be an effective alternative to intravenous phytomenadione in the correction of coagulopathies associated with obstructive liver disease. This simplifies the care of patients with deranged clotting times requiring cholangeopancreatography, particularly those to be managed as out-patients.


INTRODUCTION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography

It was first noted in 1935 that adequate amounts of vitamin K were required in the diet when chicken’s spontaneously bled following a feed that lacked this compound.1, 2 The bleeding tendency was, however, reversible if the animals were fed small amounts of cabbage.3 A conclusion was drawn that the antihaemorrhagic factor, referred to as ‘Koagulation Vitamin’ (vitamin K), was found in cereals, seeds, hog liver fat, tomatoes and kale.4, 5 Subsequently, the haemorrhagic tendency associated with obstructive liver disease also became attributable to inadequate serum vitamin K levels.6 Further work demonstrated that bleeding in this population could be reversed if a combination therapy of vitamin K and bile salts were given orally.7, 8 It is now known that vitamin K is an essential factor for the synthesis of clotting factors II (prothrombin), VII, IX and X, whilst it is also a requirement for proteins C and S synthesis, thereby having an anticoagulant role via deactivation of co-factors VIIIa and Va.9

The naturally identified vitamin K molecules are vitamin K1, predominantly found in green vegetables, and vitamin K2 synthesized by bacteria and found in fermented cheeses.9[10]–11 The two most common synthetic derivatives developed are menadione (K3), and the water soluble menadiol molecule, with conflicting published data on their potencies.12[13][14]–15 Use of these agents in clinical practice has been confined to dietary supplements in chronically deficient patients, or to correct coagulopathies due to excess coumarin ingestion. Dietary deficient patients can be given phytomenadione or menadiol, the two commercially available preparations of vitamin K, either intravenously or orally.16 Patients who are unable to absorb vitamin K due to a bile salt deficiency can also be given either formulation intravenously. However, if an oral preparation is required the water-soluble menadiol compound should be chosen as absorption is unaffected in such an environment.17

It was proposed in this prospective, randomized, controlled clinical trial, that menadiol sodium phosphate could be administered orally in place of intravenous phytomenadione to correct coagulopathies in patients with obstructive liver disease requiring endoscopic retrograde cholangeopancreatography. Full ethical approval was obtained from East Sussex, Brighton and Hove Health Authorities’ Ethics Committee. A comprehensive written and verbal explanation of the study was provided to patients entering the study, with written consent obtained for all patients recruited.

Statistics

Non-parametric analysis was chosen due to the small patient numbers. The Mann–Whitney U-test was employed to compare haematological characteristics at baseline and following administration of vitamin K. The Wilcoxon test was used to evaluate the change in international normalized ratio after each dose. A value of P < 0.05 was deemed to be significant.

METHODS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography

All patients requiring a cholangeopancreatography were screened for possible entry into the study. Clotting times were screened to identify possible entrants into the study. Those eligible could be any age, and either in or out patients. Further inclusion criteria included: biochemical and ultrasound abnormalities indicative of biliary obstruction; a baseline international normalized ratio (prothrombin time) greater than 1.2; they should not have received vitamin K supplements over the preceding 7 days; able to attend for an out patient appointment; and a willingness to participate in the study. Patients were excluded if unable to meet the above criteria and if an alternative pathological cause of malabsorption other than cholestasis was noted, e.g. Crohns Disease. They were also excluded if perceived to be non-compliant with oral therapy, had a confirmed allergy to menadiol (Synkavit) or were believed to be pregnant.

Randomization tables were used to allocate patients into each arm of the study. Those in the control group received conventional therapy with intravenous phytomenadione 10 mg as a single dose, whilst those in the active arm received oral menadiol 20 mg daily for 3 days prior to cholangeopancreatography.

RESULTS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography

A total of 244 patients were screened for inclusion into the study over an 11-month data collection period. Thirty-six patients with an international normalized ratio greater than 1.2 were identified from computer records, with nine excluded due to concomitant anticoagulation therapy. The 27 remaining patients were recruited, with one requiring an urgent cholangeopancreatography, and administered fresh frozen plasma. Twelve of the remaining 26 patients were randomized into the oral menadiol arm and 14 into the intravenous phytomenadione arm.

The median age was 67.5 years (interquartile range 58–75 years) in the menadiol group compared to 73 years (interquartile range 48–91 years) in the phytomenadione group. Only one patient was managed in primary care, with 24 patients cared for by medical teams and two by surgical teams. Biochemical and haematological data were recorded at baseline and following the administration of vitamin K. No significant differences were identified between groups at entry into the study, however, serum albumin was lower in the phytomenadione group following administration of vitamin K (P < 0.05; Table 1). The international normalized ratio decreased in all patients excluding two in the phytomenadione group who received fresh frozen plasma and were diagnosed with metastatic liver disease (Figure 1). No concomitant disease state, such as disseminating intravascular coagulation, was identified in any of the patients entering the study. All patients in the menadiol group had coagulation times corrected prior to the cholangeopancreatography examination; however, three had mildly elevated clotting times with a baseline international normalized ratio recorded at 1.3. Statistical comparison of international normalized ratio at baseline, and following administration of vitamin K, revealed no difference between the control and active arms of the study. Median international normalized ratio (interquartile range) decreased from 1.55 (1.4 to 1.9) to 1.1 (1.0–1.2), P=0.002 in the control arm vs. 1.4 (1.3–1.6) to 1.0 (0.9–1.1), P=0.003 in the active arm (Figure 2). Serum alkaline phosphatase was raised in the majority of patients (n=22), and four patients in each arm had elevated serum alanine transaminase levels. All patients had low serum albumin concentrations, and an uneventful cholangeopancreatography was performed. The majority were jaundiced due to biliary stones (Figure 1), and the rest were diagnosed with liver metastases, pancreatitis or pancreatic cancer.

Table 1.  Comparison of patient parameters—Median (Interquartile range)Thumbnail image of
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Figure 1. Individual patient characteristics.

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Figure 2. Change in international normalized ratio after vitamin K dosing.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography

To become vitamin K deficient is uncommon because daily physiological requirements of the compound are small, around 1 mcg·kg−1, and an extremely effective in vivo conservation method exists to store and release the compound when required.19

No study has compared the efficacy of oral menadiol and intravenous phytomenadione to correct coagulopathies associated with obstructive liver disease. However, evidence does exist that oral menadiol is well absorbed and prevents haemorrhagic disease of the newborn.20 It would certainly be ideal to validate this and previous work via analysis of serum menadiol and phytomenadione levels.21[22][23][24][25][26][27][28][29]–30 The outcome would identify the extent and variability of menadiol absorption, and possibly lead to a more suitable dosing regime if adopted in clinical practice. However, analysis of serum vitamin K levels may be of little value, as it has been shown that patients with primary biliary cirrhosis and low serum vitamin K levels do not necessarily have prolonged prothrombin times.25, 31 Therefore, clinical vitamin K deficiency seems uncommon, correlating well with this study as only 11% of patients screened were identified with a clotting defect.

It is important to recognize the limitations of this study whilst observing the apparent clinical effectiveness of oral menadiol compared to intravenous phytomenadione. Primarily small patient numbers will always be a complicating factor in studies of this kind, but this research did not represent a ‘sample’ group of patients as all those requiring a cholangeopancreatography were screened for possible inclusion into the study. Therefore, statistically we can assume that the results are a good reflection of clinical efficacy in this geographical area and a reasonable reflection of the general population group. Additionally, it must be noted that patients required three doses of oral menadiol, thus preventing urgent cholangeopancreatographys being performed if required. To rectify this problem, further work is needed to identify whether one large single dose of menadiol is equally effective, and the time taken to correct the coagulopathy. Another factor to consider is that the main entrance criteria was a coagulopathy identified by an international normalized ratio greater than 1.2. It may be questionable whether several patients recruited had a clinical coagulopathy necessitating the administration of vitamin K. Three patients in the menadiol arm and two in the phytomenadione arm were recruited with an international normalized ratio of only 1.3. The difference between patients being included or excluded from the study could have been minimal, i.e. an international normalized ratio of 1.26 (rounded to 1.3) included, and 1.24 (rounded to 1.2) excluded. Whilst we appreciate this limitation, it should be remembered that a coagulopathy, regardless of its severity, should be corrected to prevent bleeding during endoscopic sphinctorotemy. We must also consider the difference in international normalized ratio between the two groups, as although equivalent at baseline, the active arm had a median international normalized ratio 0.15 lower than the control arm. It maybe questioned therefore, whether patients with an international normalized ratio greater than 1.8, the highest value found in the active arm, could have this corrected via administration of oral menadiol.

CONCLUSIONS

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography

Several conclusions can be drawn from this study, the most powerful of which is an affirmation that oral menadiol appears to be an effective alternative to intravenous phytomenadione in the correction of coagulopathies associated with cholestasis. The biggest impact, if clinical practice were changed, would be noticed in the community where patient preference for oral medications and the abolishment of doctor/nurse administration time with intravenous drugs would be welcomed. Patients requiring a cholangeopancreatography could have a simple course of menadiol prior to their appointment, reducing administration costs and preventing some hospital admissions. Additionally, decreased patient risk is observed when giving oral vitamin K compared to the intravenous form, and the product is available for use under its current product licence.

ACKNOWLEDGEMENT

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography

The authors wish to thank Dr Graham Davis, School of Pharmacy, University of Brighton for his direction in this research.

Bibliography

  1. Top of page
  2. Abstract
  3. INTRODUCTION
  4. METHODS
  5. RESULTS
  6. DISCUSSION
  7. CONCLUSIONS
  8. ACKNOWLEDGEMENT
  9. Bibliography
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