Vitamin D and Cardiac Autonomic Tone in Hemodialysis (VITAH)

Vitamin D Supplementation and Cardiac Autonomic Tone in Hemodialysis Patients: A Blinded, Randomized-controlled Trial

Despite advances in treatment of conventional cardiovascular risk factors, patients with kidney disease remain at high risk for fatal cardiac events. To date, kidney disease affects approximately 2 million Canadians; however, this patient population remains grossly understudied due to the complex nature of the disease. The inadequacy of the literature to address the cardiovascular-related mortality rates in those with kidney disease reflects the urgent need for investigation of novel risk factors.

One cardiovascular risk factor which has recently been validated is the clinical measurement of cardiac autonomic tone (CAT). CAT refers to the amount of activity contributed by the stimulatory and inhibitory limbs of the cardiac autonomic nervous system, which work in concert with one another to control heart rate. CAT can be quantified computer analysis of heart rate over time, captured by a simple Holter electrocardiogram (ECG) recording. Abnormal CAT, which occurs when the autonomic system does not control heart rate properly in response to physical demands or stress, is associated with risk of adverse cardiovascular events in both healthy and high risk populations. It has recently been shown that patients with severe kidney disease demonstrate significant CAT abnormalities, thus exaggerated susceptibility to cardiac death.

Vitamin D (VD) deficiency is also common in this patient population due to the fact that the kidney plays a crucial role in VD metabolism. Given that VD deficiency is an established cardiovascular risk factor on its own, it is possible that kidney disease patients experienced compounded risk due to the combination of VD deficiency and abnormal CAT. However, no study has ever investigated whether VD deficiency influences CAT in healthy or diseased populations. To our knowledge, this will be the first trial to ever examine the effect, if any, of different VD supplementation treatments (standard of care vs. combination) on CAT in a population burdened with overwhelming risk and incidence of cardiovascular and sudden cardiac death risk.

Study Overview

• Status: Completed
• Conditions: Cardiovascular Disease; Sudden Cardiac Death
• Intervention / Treatment: Dietary supplement: Alfacalcidol; Dietary supplement: Ergocalciferol

• Study Type: Interventional
• Enrollment (Actual): 56
• Phase: Phase 2

Contacts and Locations

Study Locations

• Canada
  • Alberta
    • Calgary, Alberta, Canada, T2R 0X7
      • Sheldon M. Chumir Health Centre
    • Calgary, Alberta, Canada, T2L 2J8
      • Northland Hemodialysis Clinic
    • Calgary, Alberta, Canada, T2N 2T9
      • Foothills Medical Centre - University of Calgary

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• age ≥ 18 years
• 3x weekly hemodialysis outpatient within Calgary for at least 3 months prior to enrolment
• physician consent to participate in VD supplementation regimen
• ability and agreement to cease any VD medication for 4 weeks prior to initiation of study
• able to comprehend study and provide oral and written consent in English

Exclusion Criteria:

• any major cardiovascular event (new onset arrhythmia, hospitalization for a cardiac event) noted in patient chart within the 6 month period prior to initiation of the study
• currently on VD therapy/refusal to cease VD therapy for 4 weeks prior to initiation of study
• physician anticipates death or adverse event within the next year- known discharge from hemodialysis (transfer to peritoneal dialysis, kidney transplant)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Vitamin D Sequence 1; 6 weeks - alfacalcidol 0.25mcg + placebo 3x per week, 12 week washout, 6 weeks - alfacalcidol 0.25mcg 3x per week + 50,000IU ergocalciferol 1x per week (placebo the 2 remaining days)	Dietary supplement: Alfacalcidol; 0.25 mcg 3x per week for 6 weeks; Dietary supplement: Ergocalciferol; 50,000IU 1x per week for 6 weeks
Active Comparator: Vitamin D Treatment Sequence 2; 6 weeks - alfacalcidol 0.25mcg 3x per week + 50,000IU ergocalciferol 1x per week (placebo the 2 remaining days), 12 week washout, 6 weeks - alfacalcidol 0.25mcg + placebo 3x per week	Dietary supplement: Alfacalcidol; 0.25 mcg 3x per week for 6 weeks; Dietary supplement: Ergocalciferol; 50,000IU 1x per week for 6 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
LF:HF	Low frequency to high frequency ratio (sympathetic vs. parasympathetic cardiac autonomic power)	change from baseline to 6 weeks
LF:HF	Low frequency to high frequency ratio (sympathetic vs. parasympathetic cardiac autonomic power)	change from 6 weeks to 18 weeks
LF:HF	Low frequency to high frequency ratio (sympathetic vs. parasympathetic cardiac autonomic power)	change from 18 weeks to 24 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
SDNN	standard deviation of normal wave (heart rate variability time domain)	every 6 weeks up to 24 weeks
SDANN	standard deviation of the average normal wave (heart rate variability time domain)	every 6 weeks up to 24 weeks
pNN50%	percentage of normal waves which differ in frequency > 50 ms compared to the wave directly before (heart rate variability time domain)	every 6 weeks up to 24 weeks
LF	Low-frequency (ms squared and normalized units), thought to reflect sympathetic contribution from the cardiac autonomic nervous system	every 6 weeks up to 24 weeks
HF	High-frequency (ms squared and normalized units), thought to reflect parasympathetic contribution from the cardiac autonomic nervous system	every 6 weeks up to 24 weeks

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
25-hydroxy vitamin D		every 6 weeks up to 24 weeks
1,25-dihydroxyvitamin D		every 6 weeks up to 24 weeks
Parathyroid hormone		every 6 weeks up to 24 weeks
Calcium		every 6 weeks up to 24 weeks
Phosphate		every 6 weeks up to 24 weeks
Pre- and post-dialysis weight		every 6 weeks up to 24 weeks
Epinephrine		every 6 weeks up to 24 weeks
Norepinephrine		every 6 weeks up to 24 weeks
Renin-angiotensin system activity (circulating)	renin, angiotensin II, aldosterone	every 6 weeks up to 24 weeks

Collaborators and Investigators

• Sponsor: University of Calgary
• Collaborators: Canadian Institutes of Health Research (CIHR); Alberta Innovates Health Solutions
• Investigators: Principal Investigator: Dr. Sofia B Ahmed, MD, MMSc, University of Calgary; Principal Investigator: Dr. Derek Exner, MD, MPH, University of Calgary, Libin Cardiovascular Institute; Principal Investigator: Dr. Brenda Hemmelgarn, MD, PhD, MN, University of Calgary

Publications and helpful links

General Publications

• Lahiri MK, Kannankeril PJ, Goldberger JJ. Assessment of autonomic function in cardiovascular disease: physiological basis and prognostic implications. J Am Coll Cardiol. 2008 May 6;51(18):1725-33. doi: 10.1016/j.jacc.2008.01.038.
• Mann MC, Exner DV, Hemmelgarn BR, Turin TC, Sola DY, Ahmed SB. Impact of gender on the cardiac autonomic response to angiotensin II in healthy humans. J Appl Physiol (1985). 2012 Mar;112(6):1001-7. doi: 10.1152/japplphysiol.01207.2011. Epub 2012 Jan 5.
• Drechsler C, Pilz S, Obermayer-Pietsch B, Verduijn M, Tomaschitz A, Krane V, Espe K, Dekker F, Brandenburg V, Marz W, Ritz E, Wanner C. Vitamin D deficiency is associated with sudden cardiac death, combined cardiovascular events, and mortality in haemodialysis patients. Eur Heart J. 2010 Sep;31(18):2253-61. doi: 10.1093/eurheartj/ehq246. Epub 2010 Aug 5.
• Mann MC, Exner DV, Hemmelgarn BR, Sola DY, Turin TC, Ellis L, Ahmed SB. Vitamin D levels are associated with cardiac autonomic activity in healthy humans. Nutrients. 2013 Jun 10;5(6):2114-27. doi: 10.3390/nu5062114.
• Mann MC, Exner DV, Hemmelgarn BR, Hanley DA, Turin TC, MacRae JM, Wheeler DC, Sola DY, Ramesh S, Ahmed SB. The VITAH Trial-Vitamin D Supplementation and Cardiac Autonomic Tone in Patients with End-Stage Kidney Disease on Hemodialysis: A Blinded, Randomized Controlled Trial. Nutrients. 2016 Sep 28;8(10):608. doi: 10.3390/nu8100608.
• Mann MC, Exner DV, Hemmelgarn BR, Hanley DA, Turin TC, MacRae JM, Ahmed SB. The VITAH trial VITamin D supplementation and cardiac Autonomic tone in Hemodialysis: a blinded, randomized controlled trial. BMC Nephrol. 2014 Aug 6;15:129. doi: 10.1186/1471-2369-15-129.

Study record dates

Study Major Dates

• Study Start: January 1, 2013
• Primary Completion (Actual): March 1, 2015
• Study Completion (Actual): March 1, 2015

Study Registration Dates

• First Submitted: January 17, 2013
• First Submitted That Met QC Criteria: January 21, 2013
• First Posted (Estimate): January 24, 2013

Study Record Updates

• Last Update Posted (Estimate): August 31, 2016
• Last Update Submitted That Met QC Criteria: August 29, 2016
• Last Verified: August 1, 2016

More Information

Terms related to this study

• Keywords: vitamin D; hemodialysis; heart rate variability; sudden cardiac death; cardiac autonomic tone
• Additional Relevant MeSH Terms: Pathologic Processes; Heart Diseases; Death, Sudden; Heart Arrest; Cardiovascular Diseases; Death; Death, Sudden, Cardiac; Physiological Effects of Drugs; Micronutrients; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Vitamin D; Ergocalciferols; Alfacalcidol; Hydroxycholecalciferols
• Other Study ID Numbers: UC-Neph-2012001