Chronic Heart Failure
Conditions
Keywords
Heart failure, Vitamin D, Plasma renin activity, Renin angiotensin system
Brief summary
The renin-angiotensin system (RAS) is a regulatory system that plays an essential role in patients with chronic heart failure (CHF). Plasma renin activity (PRA) is a strong and independent predictor of outcome, also in the presence of ACE inhibitors (ACE-i) and/or angiotensin receptor blockers (ARBs). Recently, it has been shown that vitamin D regulates renin transcription by activating the vitamin D receptor (VDR). Thus, specific activation of the VDR represents a novel target for therapeutic intervention in CHF. Currently, clinical data are lacking. The investigators aim to investigate the effect of the administration of vitamin D in patients with CHF.
Interventions
DRUGVitamin D
2000 IU vitamin D daily, for 6 weeks
Sponsors
Netherlands Foundation for Cardiovascular Excellence
University Medical Center Groningen
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Out clinical patients ≥ 18 years of age, male or female. * Patients with a diagnosis of chronic heart failure (NYHA Class II, III or IV). * Patients must at least be treated with an ACE-i at a stable dose (at least enalapril 10 mg daily or any other ACE-i, e.g. ramipril, quinapril, lisinopril, fosinopril, perindopril, trandolapril; on equivalent doses, or maximum tolerated dose) or if intolerant to ACE-i with ARB therapy (Candesartan 8 mg daily or any other ARB in equivalent dose, or maximum tolerated dose) for at least 4 weeks prior to visit 1. * Patients must be treated with a beta blocker unless contraindicated or not tolerated at a stable dose for at least 4 weeks prior to visit 1 (for patients not on target dose or in absence of that medication, the reason should be documented). * Concomitant use of ACE-i and/or ARB and/or aldosterone antagonist is permitted.
Exclusion criteria
* LVEF \>45% at visit 1 (local measurement, measured within the past 12 months assessed by echocardiogram, MUGA or ventricular angiography). * History of hypersensitivity to the study drugs. * Patients with phenylketonuria. * Patients with fructose intolerance. * Current acute decompensated heart failure. * Hypercalcemia (\>2.65 mmol/l, corrected for albumin). * Hypercalciuria. * Estimated glomerular filtration fraction (eGFR) between 30 and 60 ml/min/1.73m2 as measured by the modified of diet in renal disease (MDRD) formula. * Nephrolithiasis. * Sarcoidosis. * Use of the following medication: corticosteroids, thyroxin, anti epileptic drugs, tetracyclines, quinolones * Intake of supplements containing vitamin D and/or calcium. * Acute coronary syndrome, stroke, transient ischemic attack, cardiac, carotid or major vascular surgery, percutaneous coronary intervention (PCI) or carotid angioplasty, within the past 3 months. * Coronary or carotid artery disease likely to require surgical or PCI. * Right heart failure due to severe pulmonary disease. * Diagnosis of peripartum or chemotherapy induced cardiomyopathy within the last year. * Patients with a history of heart transplant or who are on a transplant list or with LVAD device (left ventricular assistance device). * Documented ventricular arrhythmia with syncopal episodes within past 3 months that is untreated. * Documented history of ventricular tachycardia or ventricular fibrillation without ICD (internal cardiac defibrillator). * Symptomatic bradycardia, or second or third degree heart block without a pacemaker. * Implantation of a CRT (cardiac resynchronization therapy) device within prior 3 months. * Presence of hemodynamically significant mitral and /or aortic valve disease, except mitral regurgitation secondary to left ventricular dilatation. * Presence of hemodynamically significant obstructive lesions of left ventricular outflow tract, including aortic stenosis. * Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of study drugs. * Any history of pancreatic injury, pancreatitis or evidence of impaired pancreatic function/injury as indicated by abnormal lipase or amylase. * Primary liver disease considered to be life threatening. * Currently active gastritis, duodenal or gastric ulcers, or gastrointestinal/rectal bleeding during the 3 months prior to Visit 1. * History or presence of any other diseases (i.e. including malignancies) with a life expectancy of \< 5 years. * Current double-blind treatment in heart failure (HF) trials. * Participation in an investigational drug study at the time of enrollment or within the past 30 days or 5 half lives of enrollment whichever is longer. * Any surgical or medical condition that in the opinion of the investigator or medical monitor would jeopardize the evaluation of efficacy or safety. * History of noncompliance to medical regimens and patients who are considered potentially unreliable. * Pregnant or lactating women. * Treatment with any of the following drugs within the past 4 weeks prior to Visit 1 (T0): * Direct renin inhibition including Aliskiren * Intravenous vasodilator and/or inotropic drugs
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Plasma Renin Activity | 6 weeks | The primary endpoint of this study is the PRA after 6 weeks of treatment with vitamin D compared to the PRA after 6 weeks without treatment. |
Secondary
| Measure | Time frame |
|---|---|
| To evaluate the effect of vitamin D administration on plasma levels of NT-proBNP | 6 weeks |
| Safety endpoints are biochemical indices of kidney function and bone homeostasis | 6 weeks |
| To evaluate the effect of vitamin D administration on plasma values of additional markers of renin-angiotensin system activity, including angiotensin II, angiotensin converting enzyme activity and chymase activity | 6 weeks |
| To evaluate the effect of vitamin D administration on different markers of the vitamin D cascade, such as vitamin D, calcium, phosphate and PTH (parathyroid hormone) | 6 weeks |
| To evaluate the effect of vitamin D administration on extracellular matrix markers (PIIINP, PICP, PINP) and degradation markers (MMP1, MMP9, TIMP1, MMP1/TIMP1-complex) | 6 weeks |
| To evaluate the effect of vitamin D administration on NYHA-class | 6 weeks |
| To evaluate the effect of vitamin D administration on urinary levels of markers of glomerular and tubular damage | 6 weeks |
Countries
Netherlands
Outcome results
None listed