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Intervention Review

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Vitamin K supplementation for cystic fibrosis

  1. Vanitha A Jagannath1,*,
  2. Zbys Fedorowicz2,
  3. Vidhu Thaker3,
  4. Anne B Chang4

Editorial Group: Cochrane Cystic Fibrosis and Genetic Disorders Group

Published Online: 30 APR 2013

Assessed as up-to-date: 24 JAN 2013

DOI: 10.1002/14651858.CD008482.pub3


How to Cite

Jagannath VA, Fedorowicz Z, Thaker V, Chang AB. Vitamin K supplementation for cystic fibrosis. Cochrane Database of Systematic Reviews 2013, Issue 4. Art. No.: CD008482. DOI: 10.1002/14651858.CD008482.pub3.

Author Information

  1. 1

    American Mission Hospital, Department of Paediatrics, Manama, Bahrain

  2. 2

    The Cochrane Collaboration, UKCC (Bahrain Branch), Awali, Bahrain

  3. 3

    Haverstraw Pediatrics, Haverstraw, NY, USA

  4. 4

    Charles Darwin University, Menzies School of Health Research, Casuarina, Northern Territories, Australia

*Vanitha A Jagannath, Department of Paediatrics, American Mission Hospital, Manama, Manama, PO Box 1, Bahrain. kidzdoc311@gmail.com. kidzdoc311@yahoo.co.in.

Publication History

  1. Publication Status: New search for studies and content updated (no change to conclusions)
  2. Published Online: 30 APR 2013

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This is not the most recent version of the article. View current version (18 JAN 2015)

 
Characteristics of included studies [ordered by study ID]
Beker 1997

MethodsRandomised cross-over trial (2 periods of 4 weeks).
CF Clinic Children's National Medical Center (CNMC), Washington DC.
No date specified.


ParticipantsRandomised: N = 18 (8 male, 10 female); mean age 20 years (Range 13 - 35 years).

Inclusion criteria

  • confirmed diagnosis of CF by duplicate sweat test
  • clinically stable as determined by physical exam; afebrile
  • moderate lung disease based on an average radiograph score of 15 using the Brasfield scoring method
  • within or above the fifth NCHS height percentile for age and body mass index (BMI) ≥20
  • AST/ALT levels within the normal range, and normal plasma albumin levels


Exclusion criteria

  • without cholestasis or overt liver disease
  • elevated AST/ALT


Withdrawal or loss to follow-up: None reported.


InterventionsIntervention: 5 mg oral vitamin K1 supplementation per week.

Control: no supplementation.

4 weeks of first treatment then crossed over to the other treatment for a second 4-week period.

Concomitant medications permitted: cephalosporin (13); sulfamethoxazole (3); erythromycin (1); bronchodilators; standard multivitamins and 200 - 400 IU vitamin E.


OutcomesPrimary outcomes: none reported

Secondary outcomes (assessments at entry and end of each trial period)

  • plasma vitamin K1 and vitamin K1-2,3 epoxide
  • plasma PIVKA-II
  • serum osteocalcin


3-day dietary intake records were completed during each treatment period, but these did not correspond with the nutritional parameters sought as secondary outcomes for this review.

Patient compliance was verified by the trial coordinator at each visit.


NotesRandomised cross-over trial, vitamin K supplementation compared with no treatment. No wash-out period with a potential carry-over of treatment effect. No first-period data available.

"Supported in part by grants from the Board of Lady Visitors, Children's National Medical Center, Washington, DC, and the University of Maryland, College Park, Maryland."


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "randomly assigned" Page 512
Comment: insufficient information to make a clear judgement of 'Yes' or 'No'.

Allocation concealment (selection bias)Unclear riskNot reported.
Probably not done.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants: not possible; control was 'no treatment'.

Healthcare providers: not possible; control was 'no treatment'.

Outcomes assessors and data analysts: unclear.

Comment: overall judgement unclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskThere were no withdrawals and no missing or incomplete data.

Selective reporting (reporting bias)Low riskAlthough the protocol was not available all relevant outcomes appear to have been addressed.

Other biasUnclear riskQuote: "Supported in part by grants from the Board of Lady Visitors, Children's National Medical Center, Washington, DC, and the University of Maryland, College Park, Maryland."
Comment: it is unclear to what extent the support provided may have had on the results of this study. Insufficient information to assess whether an important risk of bias exists.

Drury 2008

MethodsRandomised control trial over 1-month period.
Montreal Children's Hospital Cystic Fibrosis Clinic, Canada.
Date not specified.


ParticipantsRandomised: N = 14; 8 to 18 years, gender unspecified.

Inclusion criteria

  • CF with pancreatic insufficiency. Method of CF diagnosis unreported


Exclusion criteria:

  • known liver disease (diagnosed by ultrasound, liver function tests and/or hepatomegaly)
  • supplemental therapeutic vitamin K to treat coagulopathies


Withdrawal or loss to follow-up: missing data (1) from 5 mg group at final assessment. 


InterventionsIntervention: oral administration of injectable formulation of vitamin K1 phytonadione (Sandoz Canada, Boucherville, Qc)  diluted 1 mg/1 ml. Dose 1 mg/day for 1 month.

Control: identical but dose 5 mg/day for 1 month.


OutcomesPrimary outcomes: none reported

Secondary outcomes

  • plasma vitamin K1 levels


  • serum undercarboxylated osteocalcin levels


Measured at the beginning of the trial and at the end of 1 month.


NotesThis project was funded by the Canadian CF Foundation.


Risk of bias

BiasAuthors' judgementSupport for judgement

Random sequence generation (selection bias)Unclear riskQuote: "were randomised to receive either 1 mg/day, or 5 mg/day" Page 458
Comment: insufficient information to make a clear judgement of 'Yes' or 'No'.

Allocation concealment (selection bias)Unclear riskNot reported.
Probably not done.

Blinding (performance bias and detection bias)
All outcomes
Unclear riskParticipants: not reported.

Healthcare providers: unclear.

Outcomes assessors and data analysts: unclear.

Comment: overall judgement unclear.

Incomplete outcome data (attrition bias)
All outcomes
Low riskQuote "One subject in the 5 mg group lost consciousness at the time of the second blood procurement". Pg 458
Comment: incomplete data for one participant.

Selective reporting (reporting bias)Low riskThe stated objectives of the trial appear to match the listed outcomes. There was no evidence of selective reporting of outcomes.

Other biasUnclear riskQuote: "This project was funded by the Canadian CF Foundation".
Comment: it is unclear to what extent the support provided may have had on the results of this trial. Insufficient information to assess whether an important risk of bias exists.

 
Characteristics of excluded studies [ordered by study ID]

StudyReason for exclusion

Cornelissen 1992Non-RCT.

Grey 2008Non-RCT.

Mosler 2003Non-RCT.

Nicolaidou 2006Non-RCT, non-CF control group.

Wilson 2001Uncontrolled study, non-RCT.

 
Characteristics of studies awaiting assessment [ordered by study ID]
van Hoorn 2003

MethodsCase controlled study

ParticipantsCF patients

InterventionsVitamin K in 3 different groups - no supplements, low supplements or high supplements

Outcomesserum ucOC level

NotesAwaiting inclusion until the response form the authors about randomisation in the study

van Hoorn 2008

MethodsRandomised controlled study

Participants26 patients not receiving vitamin K supplementation before

Interventions0.1 mg and 1 mg vitamin K supplementation for 2 years

OutcomesucOC levels and BMD

NotesOnly abstract is available now, likely to be included, but we will consider after we get further information from the investigators

 
Characteristics of ongoing studies [ordered by study ID]
Kuitert 2010

Trial name or titleInvestigating the effect of vitamin K supplementation on markers of bone turnover and bone density in adolescents and adults with CF

MethodsRCT

ParticipantsPatients with a diagnosis of CF (positive sweat test or genotype testing) aged over 16 years (post pubertal-stage IV Tanner), either sex, pancreatic insufficient (i.e. with a positive faecal elastase test, and requiring pancreatic enzyme supplementation) and no overt liver disease.

Interventions10 mg of menadiol phosphate (water soluble form of vitamin K) once daily orally for 12 months versus placebo.

Outcomes
  • difference in the ratio of undercarboxylated osteocalcin to total osteocalcin, measured prior to supplementation starting and at the end of the 12 months supplementation
  • total osteocalcin
  • undercarboxylated osteocalcin
  • N Terminal X (marker of bone resorption)
  • bone specific alkaline phosphatase
  • serum vitamin D
  • calcium
  • DEXA scan z and t scores of lumbar spine and femoral neck (scores adjusted for age, height and sex) measured prior to supplementation starting and at the end of the 12 months supplementation

Starting date09/05/2008

Contact informationLieske  Kuitert, Department of Respiratory Medicine, London Chest Hospital, Bonner Road, E2 9JX, London, United Kingdom

NotesStated on www.controlled-trials.com that trial completed, await publication of results.

 
Comparison 1. Comparision of 1 mg/day vs 5 mg/day oral vitamin K

Outcome or subgroup titleNo. of studiesNo. of participantsStatistical methodEffect size

 1 Serum undercarboxylated osteocalcin levels1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 2 Serum vitamin K levels1Mean Difference (IV, Fixed, 95% CI)Totals not selected

 
Table 1. Serum undercarboxylated osteocalcin (ucOC) percentage (Drury 2008)

DosenUcOC %
Baseline mean (SD)
UcOC %
End of study mean (SD)

1 mg/day746 (14.4)28 (8.26)

5 mg/day647.6 (9.45)30.2 (13.09)

 SD: standard deviation
ucOC: undercarboxylated osteocalcin
 
Table 2. Serum vitamin K levels (Drury 2008)

DosenSerum vitamin K levels (nmol/L)
Baseline mean (SD)
Serum vitamin K levels (nmol/L)
End of study mean (SD)

1 mg/day70.28 (0.25)2.52 (2.61)

5 mg/day60.15 (0.19)6.98 (9.95)

 SD: standard deviation
 
Table 3. Research recommendations based on a gap in the evidence on Vitamin K supplementation for cystic fibrosis

Core elementsIssues to considerStatus of research for this review

Evidence
(E)
What is the current state of evidence?A systematic review found only limited high quality evidence in relation to the effectiveness or otherwise of vitamin K supplementation for people with CF.

Population
(P)
Diagnosis, disease stage, comorbidity, risk factor, sex, age, ethnic group, specific inclusion or exclusion criteria, clinical settingAny age group with a diagnosis of CF (defined by sweat test or genetic testing or both). Pancreatic insufficient.

Intervention
(I)
Type, prognostic
factor
All preparations of vitamin K used as a supplement at any dose and for any duration.

Comparison
(C)
Type, prognostic factorPlacebo with a dose, frequency, duration comparable to the intervention, or no supplementation.
Trials comparing different doses and dose regimens of vitamin K will also be considered.
Compliance to be recorded via pill counts and any concomitant medications.

Outcome
(O)
Which clinical or patient related outcomes will the researcher need to measure, improve, influence or accomplish?
Which methods of measurement should be used?
Clinical outcomes related to:

  • coagulopathy
  • bone formation ie bone mineral density, DEXA scans
  • nutritional parameters; weight, height, BMI


Biochemical analysis:

  • serum levels: serum ucOC/cOC ratio
  • vitamin K-specific laboratory outcomes: plasma level of vitamin K1 (measured by HPLC), PIVKA II levels (measured by ELISA)


Quality of life:



Adverse events

Data type: continuous and dichotomous

Time stamp
(T)
Date of literature search or recommendation15 April 2010.

Study typeWhat is the most appropriate study design to address the proposed question?RCT (adequately powered/large sample size, sufficient duration)
Methods: concealment of allocation sequence
Blinding: participants and investigators, but if not feasible then outcomes assessors and data analysts should be blinded.
Setting: CF Clinic

 BMI: body mass index
CF: cystic fibrosis
cOC: carboxylated osteocalcin
DEXA: dual energy X-ray absorptiometry
ELISA: enzyme-linked immunosorbent assay
HPLC: high performance liquid chromatography
PIVKA-II: proteins induced by vitamin K absence or antagonism factor II
RCT: randomised controlled trial
ucOC: undercarboxylated osteocalcin