Favourable effects of vitamin D on cardiac function in
patients with chronic heart failure secondary to left
ventricular systolic dysfunction – the results of the MRCfunded VINDICATE Study
Klaus Witte MD, FRCP, FACC, FESC
On behalf of the VINDICATE investigators
↓IL-2, γIFN and
TNF-α, ↑IL-4 and
IL-10 production,
↓transplant
rejection
7-Dehydrocholesterol
Promyelocyte to
monocyte
differentiation
Improved cardiac
contractility, ↑LVEF
Circulating
vitamin D3
Pancreatic islet cell
insulin release
25-hydroxylase
Increased muscle
strength and
reduced fall
frequency
-ve
25 (OH) vitamin D3
Vitamin D
receptor
1-hydroxylase
Vasodilatation
-ve
1, 25 (OH)2 vitamin D3
Calcium absorption,
renin angiotensin
suppression
Parathyroid
hormone (PTH)
The pleiotropic effects
of vitamin D and their
potential importance in
heart failure
Inhibition of PTH
release
Calcium
absorption
Inhibited if
dietary
calcium
sufficient
PTH
Calcium
absorption
Calcium loading,
oxidative stress
peripheral blood
mononuclear cell
activation
Witte, Byrom, JACC HF 2014
VINDICATE
Medical Research Council - Developmental Clinical Studies:
VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Methods
Population
Inclusion criteria:
25-(OH) Vitamin D <50nmol/L (<20ng/mL)
Stable CHF due to left ventricular systolic
dysfunction (LVEF ≤ 45%)
Optimal stable medical therapy (3 months)
Ongoing symptoms (> NHYA class I)
Exclusion criteria:
Cognitive dysfunction
Significant renal dysfunction (eGFR <30)
Sarcoidosis, untreated tuberculosis
Severe airways disease (FEV1 <50%
predicted)
CHF due to untreated valvular heart
disease, anaemia or thyrotoxicosis
Intervention
Oral 100µg 25-OH vitamin D3 or non-calcium
placebo for 1 year
Provided by Cultech Ltd, Port Talbot, Wales, UK
Primary outcome
Change in 6-minute walk distance (baseline – 12
months)
Secondary outcomes
Change in cardiac function (BL-12 months)
Change in neurohormones, inflammatory markers
Sample size
Aim for 210 patients to complete
(expected difference of 30m between the
groups
at 12 m (80% power, two sided)
Registered on ClinicalTrials.gov as
NCT01619891
VINDICATE
Medical Research Council - Developmental Clinical Studies:
VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Patient disposition
Witte et al JACC 2016
VINDICATE
Medical Research Council - Developmental Clinical Studies:
VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Patient characteristics
Total (n=163)
Placebo (n=83)
Vitamin D (n=80)
129 [79.1]
62 [74.7]
67 [83.8]
68.7 (13.10)
69.0 (13.78)
68.5 (12.45)
146 [90]
74 [89]
72 [90]
Ischaemic heart disease
94 [57.7]
50 [60.2]
44 [55.0]
Non-ischaemic CDM
61 [37.4]
29 [34.9)
32 [40.0)
Valvular heart disease
8 [4.9]
4 [4.8]
4 [5.0]
Diabetes mellitus (n)[%]
37 [22.7]
20 [24.1]
17 [21.3]
30.0 (11.41)
30.3 (14.36)
29.8 (7.26)
145 [89]
71 [85.5]
74 [92.5]
Beta blockers (n)[%]
155 [95.1]
79 [95.2]
76 [95.0]
ACEi/ARB (n)[%]
150 [92.0]
76 [91.6]
74 [92.5]
61.4 (46.38)
64.4 (52.07)
58.6 (41.00)
Digoxin (n)[%]
29 [18.0]
15 [18.3]
14 [17.7]
Spironolactone (n)[%]
83 [51.2]
41 [50.0]
42 [52.5]
Device (ICD or CRT) (n)[%]
48 [29.5]
27 [32.5]
21 [26.3]
Atrial fibrillation (n)[%]
68 [45.0]
33 [42.9]
35 [47.3]
Baseline heart rate
70.5 (13.10)
72.7 (14.72)
68.2 (10.86)
Systolic BP (mmHg)
120.3 (20.81)
122.9 (22.44)
117.6 (18.74)
Diastolic BP (mmHg)
71.2 (13.21)
72.8 (14.96)
70.0 (10.99)
Male sex (n)[%]
Age
Caucasian (n)[%]
Aetiology (n)[%]
BMI (Kg/m2)
NYHA II (n)[%]
Furosemide dose (mg/day)
Witte et al JACC 2016
VINDICATE
Medical Research Council - Developmental Clinical Studies:
VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Baseline outcome variables
Total (n=163)
Placebo (n=83)
Vitamin D (n=80)
292.9 (120.35)
283.7 (116.84)
302.2 (123.81)
LVEF (%)
26.1 (10.68)
26.5 (10.62)
25.6 (10.80)
LVEDD (mm)
57.8 (7.58)
58.0 (6.49)
57.6 (8.62)
LVESD (mm)
50.3 (8.50)
50.7 (7.58)
49.8 (9.42)
LVEDV (mls)
163.0 (66.60)
164.1 (60.07)
161.8 (73.58)
LVESV (mls)
115.4 (59.39)
119.4 (53.30)
111.0 (63.58)
25(OH) Vitamin D (nmol/L)
37.3 (22.56)
36.4 (20.24)
38.2 (24.81)
Parathyroid hormone (pmol/L)
11.4 (8.09)
11.7 (7.50)
11.0 (8.75)
96 (29.3)
94.4 (29.42)
96.6 (29.26)
6 Minute walk test
Creatinine (μmol/L)
Conversion factors: vitamin D nmol/L * 0.4 = ng/mL; creatinine mmol/L * 0.11 = mg/dL;
calcium mmol/L * 4 = mg/dL; parathyroid hormone pmol/L * 9.4 = pg/mL.
Witte et al JACC 2016
VINDICATE
Medical Research Council - Developmental Clinical Studies:
VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Safety measures
• Vitamin D levels normalise
rapidly
• No adverse effects after 12
months on calcium or renal
function
• PTH levels normalised in
most (ANCOVA between
groups p<0.0001)
Witte et al JACC 2016
VINDICATE
Medical Research Council - Developmental Clinical Studies:
VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Efficacy measures
Primary efficacy outcome:
No difference in change in 6-minute walk test distance
Secondary efficacy outcomes:
Evidence of advantageous LV remodelling on echocardiography:
Reduction in dimensions
Reduction in volumes
Improvement in LV ejection fraction
Ancova
Difference in mean change
p-value
-24.11 [-65.81, 17.60]
0.255
6.07 [3.20, 8.94]
<0.001
LVEDD (mm)
-2.49 [-4.09, -0.90]
0.002
LVESD (mm)
-2.09 [-4.11, -0.06]
0.043
LVEDV (mls)
-13.11 [-25.63, -0.60]
0.040
LVESV (mls)
-12.65 [-24.76, -0.54]
0.041
Endpoint
Six minute walk distance (m)
LVEF (%)
Witte et al JACC 2016
VINDICATE
Medical Research Council - Developmental Clinical Studies:
VINDICATE: VitamIN D treating patIents with Chronic heArT failurE
Conclusions
– Vitamin D levels are low in most heart failure patients
– One year of high-dose vitamin D3 supplementation is safe
– One year of high-dose vitamin D3 leads to beneficial cardiac
remodelling
– Whether vitamin D3 improves outcomes should be the
subject of future studies
Witte et al JACC 2016
Acknowledgements and collaborators
Collaborators:
Mark T Kearney, Julian H Barth, Sue Pavitt, David A Cairns,
Graham R Law, John Greenwood, Sven Plein
Research team:
John Gierula, Rowenna Byrom, Maria F Paton, Sally
Barnes, Judith E Lowry, Haqeel A Jamil, Hemant Chumun,
Lorraine Falk, Andrea Marchant, Lisa Trueman
Partners:
Cultech, Port Talbot, Wales, UK
Funders:
Medical Research Council – DPFS grant MR/J00281X/1
Leeds Charitable Foundation
British Medical Association