VINDICATE: VitamIN D treating patIents with Chronic heArT failurE

Chronic heart failure (CHF) is a syndrome characterised by exercise intolerance due to breathlessness and fatigue in the presence of heart damage. As the population ages, and due to advances in the management of other heart problems, CHF is becoming more common, affecting around 1-2% of the United Kingdom (UK) adult population, with 6-10% of people over the age of 65 years (over 1 million people) suffering from the disorder. In 2006, 1.8% of the NHS budget was spent on the management of CHF, with 74,500 hospitalisations in England in 2000/1. There have been significant advances in therapies for CHF over the last decade, yet patients with CHF still suffer a poor quality of life, and even when optimally treated, have ongoing symptoms of breathlessness and fatigue. The outlook for patients with CHF is worse than for most cancers. They have an annual hospitalisation rate of 10% and even with maximal therapy in a specialist unit, the annual death rate is also around 10%. CHF has other features such as skeletal muscle weakness, kidney impairment, thinning of the bones (known as osteoporosis), an over-active but less effective immune system and diabetes that combine to contribute to the symptoms and poor outlook of the condition. Patients with CHF are often nutritionally deficient, but they are especially at risk of micronutrient deficiency for a variety of reasons, including poor appetite, poor mobility limiting their access to fresh fruit and vegetables, impaired absorption of nutrients and increased losses due to diuretics (water tablets). Using a combination of micronutrients, we have previously demonstrated improvements in quality of life and heart function in CHF patients.

The focus of the present study is vitamin D. Vitamin D deficiency is common in patients with CHF. In addition to its importance in bone health and calcium levels, vitamin D has widespread beneficial effects on other parts of the body including the heart, skeletal muscle, kidney, immune system and insulin production. We propose therefore that vitamin D deficiency is a correctable contributor to the reduced survival and poor quality of life in patients with CHF. Our aim is to determine the effect of high-dose vitamin D supplementation in patients with CHF on maximal and sub-maximal exercise capacity, heart function, symptoms and quality of life. We will screen 350 stable CHF patients under follow-up in the Leeds and Hull Heart Failure Clinics with the aim of randomising 250 to 100mcg vitamin D3 or placebo daily for 12 months. We have conducted a pilot feasibility study in 60 patients which has demonstrated the tolerability, biochemical efficacy and safety of our supplement. The pilot study has also shown promising results on submaximal exercise tolerance (6-minute walk distance) and symptoms. From these data we have estimated our sample size of 250 (125 in each arm).

In order to successfully complete this project, we have assembled two teams of experienced clinical researchers in the field of CHF in centres geographically in close proximity to each other (Leeds and Hull) to ensure adequate recruitment. The study has been designed in collaboration with, and will be supported throughout, by the Division of Biostatistics at the University of Leeds and data from both sites will be handled by the Data Management Group of the Leeds Institute for Genetics Health and Therapeutics who will design a database for the VINDICATE project. We have involved an experienced methodologist and in addition to the involvement of the patient consultation group that helped design the project, two patient representatives will sit on the steering committee.

DESIGN: Two-centre double-blind randomised placebo-controlled study of 250 patients with stable CHF.
INCLUSION CRITERIA: 1. Class II and III heart failure with left ventricular (LV) systolic dysfunction (LV ejection fraction

VINDICATE will explore the benefits of vitamin D supplementation on patients with chronic heart failure. Improvements in walk distance or symptoms are potentially of great importance to patients since submaximal exercise intolerance with fatigue and breathlessness is a major complaint in CHF. Hence vitamin D could improve the quality of life of millions of CHF patients.
In addition, improvements in cardiac function often relate to improvements in prognosis. If vitamin D improved cardiac function therefore, patients might live longer, but additionally might also at least initially have lower hospitalisation rates. Since vitamin D is inexpensive cost per quality of life year gained is likely to be very low.

Furthermore, unlike most new therapies, the cost-effectiveness of vitamin D is likely to be high. Hence, once sufficient data have been collected, adoption onto guidelines should be rapid. This will lead to a more rapid uptake than usual for new treatments for heart failure such that large numbers of patients can immediately begin to benefit from the supplement.

If we can identify a benefit on submaximal exercise capacity of vitamin D, we will need to explore mechanisms. It is likely that much of the benefit of vitamin D originates from improved skeletal muscle function. VINDICATE and subsequent mechanistic work could easily stimulate a renewed interest in the skeletal muscles in CHF and greater collaboration between sports science, exercise physiologists and academic clinicians to explore why skeletal muscles are dysfunctional in CHF and how they can be encouraged to function more efficiently.

The management of osteoporosis has been hampered by the use of low-dose vitamin D. If VINDICATE shows safety, it might at last be time to explore the benefits of a higher-dose supplement in patients with osteoporosis.

Other potential beneficiaries of VINDICATE might be patients with inflammatory and auto-immune disorders. In small studies, vitamin D has already been shown to reduce rejection in transplant recipients, delay relapse in multiple sclerosis patients, and improve glucose control in diabetics. In each of these promising situations, large studies need to be undertaken, but research funding for micronutrient interventions including vitamin D is been limited by the lack of commercial support and a scepticism amongst clinicians. By using scientifically rigorous methodology in a study exploring a dietary intervention, albeit with a powerful rationale based upon good fundamental science, VINDICATE could jump-start a whole new sector of research in several chronic, disabling and life-threatening conditions.