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Favourable effects of vitamin D on cardiac function in patients with chronic heart failure secondary to left ventricular systolic dysfunction the results of the MRC- funded VINDICATE Study Klaus Witte MD, FRCP, FACC, FESC On behalf of the

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Favourable effects of vitamin D on cardiac function in patients with chronic heart failure secondary to left ventricular systolic dysfunction – the results of the MRC- funded VINDICATE Study

Klaus Witte MD, FRCP, FACC, FESC On behalf of the VINDICATE investigators

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Promyelocyte to monocyte differentiation

7-Dehydrocholesterol Circulating vitamin D3 25 (OH) vitamin D3 1, 25 (OH)2 vitamin D3

25-hydroxylase 1-hydroxylase

  • ve
  • ve

Vitamin D receptor Calcium absorption Calcium absorption Calcium absorption, renin angiotensin suppression PTH Inhibition of PTH release ↓IL-2, γIFN and TNF-α, ↑IL-4 and IL-10 production, ↓transplant rejection Increased muscle strength and reduced fall frequency Inhibited if dietary calcium sufficient

The pleiotropic effects

  • f vitamin D and their

potential importance in heart failure

Pancreatic islet cell insulin release Improved cardiac contractility, ↑LVEF Calcium loading,

  • xidative stress

peripheral blood mononuclear cell activation Parathyroid hormone (PTH) Vasodilatation

Witte, Byrom, JACC HF 2014

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Medical Research Council - Developmental Clinical Studies: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

VINDICATE

Popula'on

Inclusion criteria:

25-(OH) Vitamin D <50nmol/L (<20ng/mL) Stable CHF due to leF ventricular systolic dysfunc'on (LVEF ≤ 45%) Op'mal stable medical therapy (3 months) Ongoing symptoms (> NHYA class I)

Exclusion criteria:

Cogni've dysfunc'on Significant renal dysfunc'on (eGFR <30) Sarcoidosis, untreated tuberculosis Severe airways disease (FEV1 <50% predicted) CHF due to untreated valvular heart disease, anaemia or thyrotoxicosis

Interven'on

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 func'on (BL-12 months) Change in neurohormones, inflammatory markers

Sample size

Aim for 210 pa'ents to complete

(expected difference of 30m between the groups at 12 m (80% power, two sided)

Registered on ClinicalTrials.gov as NCT01619891

Methods

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Medical Research Council - Developmental Clinical Studies: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

VINDICATE

Pa'ent disposi'on

Witte et al JACC 2016

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Pa'ent characteris'cs

Medical Research Council - Developmental Clinical Studies: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

VINDICATE

Total (n=163) Placebo (n=83) Vitamin D (n=80) Male sex (n)[%] 129 [79.1] 62 [74.7] 67 [83.8] Age 68.7 (13.10) 69.0 (13.78) 68.5 (12.45) Caucasian (n)[%] 146 [90] 74 [89] 72 [90] AeEology (n)[%] 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] BMI (Kg/m2) 30.0 (11.41) 30.3 (14.36) 29.8 (7.26) NYHA II (n)[%] 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] Furosemide dose (mg/day) 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 fibrillaEon (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)

Witte et al JACC 2016

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Total (n=163) Placebo (n=83) Vitamin D (n=80) 6 Minute walk test 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) CreaEnine (μmol/L) 96 (29.3) 94.4 (29.42) 96.6 (29.26)

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.

Baseline outcome variables

Medical Research Council - Developmental Clinical Studies: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

VINDICATE Witte et al JACC 2016

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  • Vitamin D levels normalise

rapidly

  • No adverse effects aFer 12

months on calcium or renal func'on

  • PTH levels normalised in

most (ANCOVA between groups p<0.0001)

Medical Research Council - Developmental Clinical Studies: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

VINDICATE

Safety measures

Witte et al JACC 2016

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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: Reduc'on in dimensions Reduc'on in volumes Improvement in LV ejec'on frac'on

Endpoint Ancova Difference in mean change p-value Six minute walk distance (m)

  • 24.11 [-65.81, 17.60]

0.255 LVEF (%) 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

Medical Research Council - Developmental Clinical Studies: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

VINDICATE Witte et al JACC 2016

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– Vitamin D levels are low in most heart failure pa'ents – One year of high-dose vitamin D3 supplementa'on 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

Medical Research Council - Developmental Clinical Studies: VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

VINDICATE

Conclusions

Witte et al JACC 2016

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Acknowledgements and collaborators

Collaborators:

Mark T Kearney, Julian H Barth, Sue Paviq, 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 Founda'on Bri'sh Medical Associa'on