Clinical trial NCT04247087: Effects of Fhytomenadione on Coronary Artery Calcification of Hemodialysis Patients
Official title: Effects of Fhytomenadione on Coronary Artery Calcification of Hemodialysis Patients. Randomized Clinical Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Coronary Calcification
Keywords: coronary calcification
phytomenadione
chronic kidney disease
hemodialysis
Lead sponsor: Instituto Mexicano del Seguro Social
Sponsor class: OTHER_GOV
Collaborators: name: Marco Antonio Ocampo Apolonio
name: Rodolfo Guardado Mendoza
name: Texar Alfonso Pereyra Nobara
First posted: 2020-01-29
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: randomized clinical trial with double blinding compared to placebo
Primary purpose: TREATMENT

Brief 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.

Eligibility criteria: 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.

Exclusion 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
* Patients who undergo renal transplantation during the follow-up period
* Patients who change the modality to peritoneal dialysis during the follow-up period
* Patients who are known allergy to vitamin K

Primary outcomes:
measure: coronary calcium score
timeFrame: 12 months
Secondary outcomes:
measure: cardiovascular events
timeFrame: 12 months
Other outcomes:
Locations:
city: Leon
country: Mexico
facility: Hospital de Alta Especialidad No. 1 Bajío, Boulevard Adolfo López Mateos esquina Insurgentes S/N, colonia Los Paraísos
state: Guanajuato
Study officials:
affiliation: Instituto Mexicano del Seguro Social
name: Hilda E Macias Cervantes, Doctor
role: PRINCIPAL_INVESTIGATOR
affiliation: Instituto Mexicano del Seguro Social
name: Marco A Ocampo Apolonio, Doctor
role: STUDY_CHAIR
affiliation: Universidad de Guanajuato
name: Rodolfo Guardado Mendonza, Doctor
role: STUDY_DIRECTOR
affiliation: Instituto Mexicano del Seguro Social
name: Texar A Pereyra Nobara, Doctor
role: STUDY_CHAIR
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