Effects of Fhytomenadione on Coronary Artery Calcification of Hemodialysis Patients
Condition: Coronary Calcification
MeSH terms: Calcinosis
Study type: Interventional

Summary: 
      Until 2013 the reported incidence of chronic kidney disease varied widely between countries,
      reporting the highest prevalence Taiwan, the region of Jalisco in Mexico and United States,
      with 458, 421 and 363 individuals per million inhabitants respectively. Mexico has around
      52,000 patients in replacement therapies, of which 80% of patients are treated in the
      Instituto Mexicano del Seguro Social (IMSS).

      In each stage of renal disease the principal cause of mortality is cardiovascular disease.
      The risk of cardiovascular mortality is greater than the general population. Arterial
      calcification, a marker of atherosclerosis and cardiovascular mortality predictor is common
      in chronic kidney disease. The presence of arterial calcification leads to an increase in
      arterial stiffness and to a decrease in coronary perfusion resulting in cardiac hypertrophy
      and myocardial ischemia.

      The presence of traditional cardiovascular risk factors like diabetes, hypertension,
      hyperlipidemia and old age cannot fully explain the high prevalence of atherosclerosis and
      arterial calcification in chronic kidney disease. Another specific factors related to chronic
      kidney disease, like hyperphosphatemia, high calcium concentration in dialysis solutions, use
      of high doses of vitamin D for the management of hyperparathyroidism has been shown to
      positively influence development of arterial calcification. Invitro studies show that in
      presence of hyperphosphatemia smooth muscle cells are transformed into osteoblast-like cells
      that can express proteins that regulate mineralization. Two of this proteins, the matrix Gla
      protein (MGP) and osteocalcin (OC) are regulators of tissue mineralization in arterial walls
      and bones respectively. Vitamin K is required as cofactor in the gamma-carboxylation process
      of several extracellular matrix proteins, converting inactive carboxylated proteins to
      carboxylated active proteins. Prothrombin and coagulation factors 7,9 y 10 require vitamin K2
      for its carboxylation process, while osteocalcin and the matrix Gal protein require vitamin
      K1. Matrix Gla protein is a calcification inhibitor that plays an important role in the
      prevention of arterial calcification. For carboxylation and correct function of the MGP is
      necessary an enzymatic cofactor, vitamin K; this is corroborated in the fact that the
      antagonism of vitamin K with warfarin antagonizes the carboxylation of MGP and produces rapid
      arterial calcification.

      There are currently no studies evaluating vitamin K in the prevention of vascular
      calcification in patients with chronic kidney disease, therefore, the role of vitamin K in
      the patient with kidney disease needs to be clarified with randomized controlled studies, in
      which the target will be this population of patients at high risk. The aim of this study is
      evaluate the effect of phytomenadione on coronary artery calcification of patients on
      hemodialysis compared to placebo, our research hypothesis is that phytomenadione slows the
      progression and favors the regression of coronary arterial calcification in patients on
      hemodialysis compared to placebo, evaluating the coronary calcium score by coronary
      tomography. As secondary objectives was determine changes in the baseline coronary calcium
      score and at 12 months of use of phytomenadione and presence of cardiovascular events like
      acute myocardial infarction, unstable angina and death of cardiac cause. The intervention
      group received phytomenadione 10 mg (1 vial in the venous line of the extracorporeal
      hemodialysis circuit) post hemodialysis 3 times a week for 12 months and the control group 1
      vial of placebo solution (solution for injection in the venous line of the extracorporeal
      hemodialysis circuit) post hemodialysis 3 times a week for 12 months. The follow-up of the
      patients was for 12 months, at the end of the follow-up, a coronary control tomography was
      performed by the Radiology Department to assess the final calcium score. Relative risk
      measurement (RR), absolute risk reduction (ARR) and number to be treated (NTT) were
      performed.
    

Detailed description: 
      In our hospital (Unidad Medica de Alta Especialidad No. 1 Bajío), there are about 130
      patients on hemodialysis and estimation of cardiovascular risk is done through basic studies
      as the lipid profile, electrocardiogram and echocardiogram and its management is determined
      by classical interventions like diabetes control, hypertension and statins use, which have
      not shown an increase in patient survival, and it is clear that more dramatic interventions
      to normalize phosphate, such as intensive dialysis and even renal transplantation, cannot
      reverse vascular calcification. This may be because the reversion process needs to be
      activated at the cellular level, interventions such as the use of vitamin K as a strong
      tissue calcification inhibitor can be an active tool for the reversal of vascular
      calcification in chronic kidney disease.

      By demonstrating a reversal of coronary calcification with the use of vitamin K, the
      incidence of cardiovascular events can be reduced, thus decreasing the progression of
      coronary atherosclerosis and the risk of acute myocardial infarction. The use of vitamin K
      may represent an economic intervention that could be implemented in the other hospital
      centers as a primary part of management in patients with chronic kidney disease in
      hemodialysis. Based on this we ask the following research question: ¿What is the effect of
      phytomenadione on the calcification of coronary arteries in patients on hemodialysis compared
      to placebo?. Our research hypothesis was that phytomenadione slows the progression and favors
      the regression of coronary arterial calcification in patients on hemodialysis compared to
      placebo.

      A randomized clinical trial was designed with double blinding compared to placebo, the type
      of sampling was simple random probabilistic and the universe of study patients on
      hemodialysis of the Unidad Médica de Alta Especialidad No. 1 Bajío, with diagnosis of chronic
      kidney disease of any etiology that meet the tomographic criterion of a coronary calcium
      score of 10 Agatston units.

      The selection criteria were as follows:

      Inclusion criteria:

      Patients with chronic kidney disease in hemodialysis Patients who have 6 months or more on
      hemodialysis Patients over 18 years Patients that meet the tomographic criterion of a
      coronary calcium score of 10 Agatston units.

      Male and female right-holders of the IMSS

      No Inclusion criteria:

      Patients in previous or current treatment with phytomenadione Coronary stent patients
      Patients with arrhythmias and requiring oral anticoagulation with warfarin or acenocoumarin
      Pregnant patients

      Exclusion criteria:

      Patients who undergo renal transplantation during the follow-up period Patients who change
      the modality to peritoneal dialysis during the follow-up period

      Elimination criteria:

      Patients who wish to leave the study Patients allergic to vitamin K The start date of the
      study was after approval by the Electronic Registration System of the Health Research
      Coordination (SIRELCIS by its acronym in spanish) until the entire universe is completed and
      12 months follow-up of the intervention. This work was approved by the local research and
      ethics committee, approved with the registration number R-2017-501-16.

      The sample size was calculated based on the article by Block et al (2005) where the annual
      proportion of coronary artery calcification in patients on hemodialysis was evaluated with
      placebo use, which was 88%. Assuming that with the use of vitamin K the proportion of
      patients presenting with progression of coronary artery calcification will be 70%, plus an
      alpha error of 0.05, a test power of 80% and a single tail, a size of 27 patients per group
      was obtained, considering a loss of 10% the sample was increased to 30 patients per group.

      The methodology was as follows: within the population of hemodialysis patients, patients who
      met the inclusion criteria were sought, once the participation in the study was accepted and
      an informed consent was signed, a coronary tomography was performed and, after completing the
      sample size, the patients were randomized using a random number letter.

      Coronary tomography was performed and interpreted by UMAE No. 1 Radiology staff, who had no
      knowledge about the study groups or their intervention.

      To the study group was administered 10 mg of phytomenadione (1 vial in the venous line of the
      extracorporeal hemodialysis circuit) post hemodialysis 3 times a week, and to the group
      control a placebo solution post hemodialysis 3 times a week; both vitamin K and placebo were
      provided by the hospital pharmacy. After each application, both the drug and the placebo were
      monitored for adverse effects.

      The follow-up of the patients was for 12 months, at the end of the follow-up, a coronary
      control tomography was performed by the Radiology Department to assess the final calcium
      score.

      The laboratory studies were processed in the hospital's laboratory and are part of the
      follow-up studies of patients with chronic kidney disease, they were requested upon admission
      of the patients in the study and at the end of the 12-month follow-up.

      The results are presented with descriptive statistics with mean and standard deviation or
      median with confidence intervals according to the type of variable.

      Qualitative variables were analyzed using Chi square or exact Fisher test. Quantitative
      variables using student's T or Mann Withney's W in case of not having normal distribution.

      To compare coronary artery calcification between the vitamin K and placebo groups, they were
      compared using T from independent samples or U Mann Withney, and to compare the change
      between baseline and final coronary calcification in both the intervention group and the
      control group, the coronary calcium score delta was calculated, and a paired student's T or
      Wilcoxon test was performed. p values menor 0.05 were considered as significant.

      Likewise, relative risk measurement (RR), absolute risk reduction (ARR) and number to be
      treated (NTT) were performed.
    

Intervention name(s): phytomenadione; placebo solution
Intervention type(s): Drug; Drug
Intervention description(s): phytomenadione 10 mg (1 vial in the venous line of the extracorporeal hemodialysis circuit) post hemodialysis 3 times a week for 12 months; 1 vial of placebo solution (solution for injection in the venous line of the extracorporeal hemodialysis circuit) post hemodialysis 3 times a week for 12 months
Other intervention name(s): vitamin K; solution for injection
Intervention MeSH terms: Vitamin K; Vitamin K 1; Pharmaceutical Solutions
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: randomized clinical trial with double blinding compared to placebo
Masking: Double (Participant, Outcomes Assessor)
Primary purpose: Treatment
Keywords: coronary calcification; phytomenadione; chronic kidney disease; hemodialysis