Effects of Fhytomenadione on Coronary Artery Calcification of Hemodialysis Patients
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|ClinicalTrials.gov Identifier: NCT04247087|
Recruitment Status : Completed
First Posted : January 29, 2020
Last Update Posted : January 29, 2020
|First Submitted Date ICMJE||January 24, 2020|
|First Posted Date ICMJE||January 29, 2020|
|Last Update Posted Date||January 29, 2020|
|Actual Study Start Date ICMJE||September 7, 2017|
|Actual Primary Completion Date||September 27, 2019 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||coronary calcium score [ Time Frame: 12 months ]
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 interpreted by Radiology staff, who had no knowledge about the study groups or their intervention. Those patients who fulfilled the coronary calcification tomographic criterion defined as coronary calcium score of 10 Agatston units were randomized to receive the intervention or the placebo. At the end of the 12 month follow-up, a coronary tomography was performed again to quantify the final Agatston score
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||No Changes Posted|
|Current Secondary Outcome Measures ICMJE
||cardiovascular events [ Time Frame: 12 months ]
determine presence of cardiovascular events like acute myocardial infarction, unstable angina and death of cardiac cause during follow-up. The presence of events will be determined according to the clinical record in the patient's file
|Original Secondary Outcome Measures ICMJE||Same as current|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Effects of Fhytomenadione on Coronary Artery Calcification of Hemodialysis Patients|
|Official Title ICMJE||Effects of Fhytomenadione on Coronary Artery Calcification of Hemodialysis Patients. Randomized Clinical Trial|
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.
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:
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
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 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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Not Applicable|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
randomized clinical trial with double blinding compared to placeboMasking: Double (Participant, Outcomes Assessor)
Patients were randomly assigned to receive intravenous vitamin K or placebo solution. Coronary tomography was performed and interpreted by Radiology staff, who had no knowledge about the study groups or their interventionPrimary Purpose: Treatment
|Condition ICMJE||Coronary Calcification|
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Actual Enrollment ICMJE||Same as current|
|Actual Study Completion Date ICMJE||January 2, 2020|
|Actual Primary Completion Date||September 27, 2019 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years to 70 Years (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Mexico|
|Removed Location Countries|
|NCT Number ICMJE||NCT04247087|
|Other Study ID Numbers ICMJE||1|
|Has Data Monitoring Committee||No|
|U.S. FDA-regulated Product||
|IPD Sharing Statement ICMJE||
|Responsible Party||Hilda Elizabeth Macias Cervantes, Instituto Mexicano del Seguro Social|
|Study Sponsor ICMJE||Instituto Mexicano del Seguro Social|
|PRS Account||Instituto Mexicano del Seguro Social|
|Verification Date||January 2020|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP