The Effects of Vitamin D Supplementation on Physical Function and Quality of Life in Older Patients With Heart FailureCLINICAL PERSPECTIVE
A Randomized Controlled Trial
Background— Low 25-hydroxyvitamin D levels, commonly found in older patients with heart failure, may contribute to the chronic inflammation and skeletal myopathy that lead to poor exercise tolerance. We tested whether vitamin D supplementation of patients with heart failure and vitamin D insufficiency can improve physical function and quality of life.
Methods and Results— In a randomized, parallel group, double-blind, placebo-controlled trial, patients with systolic heart failure aged ≥70 years with 25-hydroxyvitamin D levels <50 nmol/L (20 ng/mL) received 100 000 U of oral vitamin D2 or placebo at baseline and 10 weeks. Outcomes measured at baseline, 10 weeks, and 20 weeks were 6-minute walk distance, quality of life (Minnesota score), daily activity measured by accelerometry, Functional Limitations Profile, B-type natriuretic peptide, and tumor necrosis factor-α. Participants in the vitamin D group had an increase in their 25-hydroxyvitamin D levels compared with placebo at 10 weeks (22.9 versus 2.3 nmol/L [9.2 versus 0.9 ng/mL]; P<0.001) and maintained this increase at 20 weeks. The 6-minute walk did not improve in the treatment group relative to placebo. No significant benefit was seen on timed up and go testing, subjective measures of function, daily activity, or tumor necrosis factor. Quality of life worsened by a small, but significant amount in the treatment group relative to placebo. B-type natriuretic peptide decreased in the treatment group relative to placebo (−22 versus +78 pg/mL at 10 weeks; P=0.04).
Conclusions— Vitamin D supplementation did not improve functional capacity or quality of life in older patients with heart failure with vitamin D insufficiency.
Clinical Trial Registration— www.controlled-trials.com. Identifier: ISRCTN51372896.
Received September 8, 2009; accepted January 7, 2010.
The median age at diagnosis for persons with heart failure is 76 years in the United Kingdom,1 and 10% of people aged ≥80 years have heart failure.2 Despite the introduction of neurohormonal blocking agents over the past 25 years, physical function and quality of life remain poor among many older patients with this condition.3,4 New approaches to relieving the burden of morbidity in heart failure are therefore needed.
Editorial see p 183
Clinical Perspective on p 195
Recent work has suggested that vitamin D insufficiency is common in patients with heart failure5,6 and it is known to be more common in old age. In patients without heart failure, it is associated with reduced skeletal muscle strength and reduced exercise capacity. Vitamin D now is recognized to have several interesting biological effects in addition to calcium and bone homeostasis. It possesses antiinflammatory properties,7 may suppress renin levels,8 and can enhance both muscle reaction to sway9 and muscle strength.10 In patients with diabetes, vitamin D supplementation improves endothelial function,11 and in patients with end-stage renal failure, vitamin D has positive effects on cardiac remodeling12; therefore, it is possible that vitamin D supplementation could improve the skeletal myopathy that is responsible for much of the poor exercise tolerance and symptom burden in older patients with heart failure13 as well as improve underlying cardiovascular function and ameliorate the proinflammatory state found in heart failure. All these effects potentially could lead to improvements in exercise capacity and, consequently, physical function and quality of life. Therefore, we performed a randomized controlled trial to examine whether vitamin D supplementation could improve parameters that are directly relevant to older people with heart failure (ie, exercise capacity, physical function, and quality of life).
Study Design and Population
The study was a parallel-group, double-blind, randomized, placebo-controlled trial. Participants were eligible for inclusion if they were aged ≥70 years with a previously recorded clinical diagnosis of chronic heart failure, previously documented left ventricular systolic dysfunction by echocardiography, radionuclide ventriculography, or angiography as part of their usual clinical care and had New York Heart Association class II or III symptoms. Participants were required to have a screening 25-hydroxyvitamin D level of <50 nmol/L (20 ng/mL) to be eligible for inclusion.
Exclusion criteria were as follows: a clinical diagnosis of osteomalacia, under investigation for recurrent falls, already taking vitamin D supplements, moderate to severe cognitive impairment (defined as a Folstein mini-mental state examination <15 out of 30), serum creatinine >200 μmol/L, liver function tests (bilirubin, alanine aminotransferase, and alkaline phosphatase) >3 times the upper limit of the local reference range, systolic blood pressure <90 mm Hg, albumin-adjusted calcium (>2.55 mmol/L or <2.20 mmol/L), and metastatic malignancy. We also excluded patients who were wheelchair bound and, thus, would be unable to perform the primary outcome as well as patients unwilling or unable to give informed consent.
Written informed consent was obtained from all participants during a screening visit. The study conformed to the principles of the Declaration of Helsinki and was approved by Fife and Forth Valley Research Ethics Committee (08/S0501/13). The trial was prospectively registered with the Current Controlled Trials database (ISRCTN51372896).
Eligible participants were recruited from primary and secondary care in Tayside and Fife health board areas in Scotland, United Kingdom. Participants were patients discharged from medical, cardiology, and Medicine for the Elderly wards; Medicine for the Elderly, cardiology, and heart failure clinics; primary care patient lists; and community-dwelling patients following local media publicity.
Randomization and Treatment Allocation
Randomization was performed using computer-generated random number tables by DHP Pharmaceuticals (Gwent, United Kingdom), who overencapsulated the study medication to render it identical to placebo. Code allocation was concealed from the research nurse and investigators until after data analysis was complete. An oral dose (100 000 U ergocalciferol or placebo) was administered after baseline outcome measures were performed and was repeated at 10 weeks. Administration was supervised in the participant’s own home by the research nurse, who observed ingestion to ensure 100% adherence. This dose of vitamin D has been safely used in previous intervention studies, has been shown to increase 25-hydroxyvitamin D levels by ≈20 nmol/L (12 ng/mL),14 and has been shown to have beneficial effects on blood pressure and endothelial function in other cardiovascular disease states.11
Outcomes were measured at baseline, 10 weeks, and 20 weeks. The primary outcome measure was the 6-minute walk test,15 a measure of submaximal exercise capacity. The 6-minute walk reflects the type of aerobic activity that most older persons with heart failure would undertake, and unlike maximal exercise testing on treadmill or cycles, the test can be performed by persons using walking aids or with significant comorbid musculoskeletal disease. It is, therefore, an outcome with direct relevance to patients. The test has been validated for use in older patients with heart failure16; the minimum clinically important change for the 6-minute walk is 30 m in older patients with heart failure. Tests were performed using a flat, straight, indoor 25-m course. Participants were asked to refrain from cigarettes or caffeine for at least 2 hours before the test. Participants used their usual walking aids and received standardized encouragement at regular intervals.
Secondary Outcome Measures
Timed Up and Go Test
Participants were asked to stand up from a chair, using their arms to assist; walk 3 m, using their customary walking aid; turn; and sit back down on the chair. The test time was recorded to the nearest 10th of a second by an observer using a stopwatch. The test is widely used in measuring clinically significant changes in mobility in older frail patients; reflects important daily physical functions, such as the ability to rise from a chair and walk around the house; correlates with level of dependency17; and has been shown to improve with vitamin D supplementation in patients without heart failure.10
Daily Physical Activity Levels
Physical activity levels were measured objectively using the RT3 Triaxial Research Tracker device that continuously tracks activity through piezoelectric accelerometry, measuring motion in 3D. Participants were asked to wear it for 7 consecutive days during their waking hours in the week before visits. The device has previously been validated in older persons18 and has successfully shown changes in activity with interventions in older patients with heart failure.19
Health Status and Health-Related Quality of Life
We used the Minnesota Living With Heart Failure questionnaire, a disease-specific tool20 that is validated for use in older patients with heart failure, and the Functional Limitations Profile, a general health status tool that is a modified UK version of the Sickness Impact Profile.21
Cardiovascular and Inflammatory Markers
Blood samples were centrifuged immediately after collection, and supernatants were stored at −20°C (−70°C for B-type natriuretic peptide [BNP]) and processed as a batch at the end of the study. Samples from each time point for a particular participant were run on the same assay batch. Serum 25-hydroxyvitamin D levels at baseline, 10 weeks, and 20 weeks were measured using radioimmunoassay. This assay has equal sensitivity to 25-hydroxyvitamin D2 and 25-hydroxyvitamin D3.22 BNP, aldosterone, and renin also were measured using radioimmunoassay, with intraassay coefficients of variation of 13.2%, 5.5%, and 4.8%, respectively. Tumor necrosis factor-α was measured using ELISA, with an intraassay coefficient of variation of 13.2%.
Additional data were gathered on age, cognitive state, number of medications, place of residence, and any formal help in the home. Serum urea and electrolytes (including corrected calcium and phosphate) were measured at baseline, 10 weeks, and 20 weeks; parathyroid hormone levels were recorded at baseline and 10 weeks. All adverse events, including hospital admission, morbidity, and mortality, were recorded.
Statistical Analyses and Sample Size Calculation
Based on previous data from our group, we anticipated a mean distance of 274 m walked in 6 minutes.23 We predicted that a sample size of 94 participants (47 per group) would have 90% power to detect an increase in 6-minute walking distance (assuming an SD of 30 m) of 20 m at P<0.05. Studies of the relationship between patients’ global rating of change in condition and 6-minute walking distance have indicated that 30 m is the minimum clinically important improvement.16 We aimed to recruit 136 participants in anticipation of a 30% dropout rate at 20 weeks to yield a final evaluable sample of 94 participants.
Data were entered and analyzed using the SPSS version 15. All analyses were completed before breaking the study randomization code. Differences between groups at baseline were compared using Student t test for continuous variables or Mann-Whitney U test for nonnormally distributed continuous variables. Pearson χ2 test was used to compare categorical variables. Changes in all of the main outcome measures were normally distributed except for BNP. Changes were analyzed using 2-sample Student t test. Change in BNP was log transformed before t testing. For 6-minute walk and daily activity, percentage change from baseline was calculated to compensate for the wide ranges of values seen in these outcomes and to adjust for differences in baseline values in a similar way to covariate analysis.
To compensate for differences in the groups at baseline, the difference in change in the primary outcome at 20 weeks was adjusted for baseline variables exhibiting between-group differences at a significance level of P<0.2. A sensitivity analysis also was performed for the primary outcome, assuming that participants with missing primary outcome data could not walk and, therefore, had a 6-minute walk distance of 0 m. Multiple imputation was not performed because the missing data were not missing at random, thus violating one of the key assumptions underpinning multiple imputation.
Four hundred eighty-seven potentially suitable participants were identified and invited for screening. A total of 173 patients underwent screening visits for the study (Figure). Of these, 105 were randomized into the study between June 2005 and October 2008, baseline details of whom are shown in Table 1. All participants were of white European origin.
Effects on 25-Hydroxyvitamin D Levels
Table 2 shows the effect of vitamin D supplementation on calcium, phosphate, parathyroid hormone, and 25-hydroxyvitamin D levels. As expected, vitamin D supplementation caused a significant increase in 25-hydroxyvitamin D level in the treatment group, with a corresponding small, but significant increase in adjusted calcium levels.
Forty-six (88%) participants in the placebo group completed the 10-week 6-minute walk test compared with 45 (85%) in the treatment group. At 20 weeks, 42 patients in each group completed the 6-minute walk test (81% in the placebo group versus 79% in the treatment group). Reasons for failure to perform the walk test included death, illness, and poor health precluding the ability to stand and walk without human assistance. Unadjusted between-group comparison of the change in 6-minute walk between baseline and follow-up showed no significant improvement in the treatment group compared with placebo. The 95% CI fell well short of the minimum clinically important change of 30 m. Outcome measures are shown in Table 3. Adjusted analyses were conducted on the change in 6-minute walk between baseline and week 20 to compensate for differences in key variables at baseline; results are shown in Table 4 and confirm that no improvement was seen with vitamin D supplementation. A post hoc power calculation using actual, rather than predicted SDs for the change in 6-minute walk showed that our sample had 96% power to detect a 30-m change in 6-minute walk distance at 20 weeks. Similarly, the study had 92% power to detect a 4-second improvement in timed up and go at 20 weeks and 89% power to detect a 70-point change in the Functional Limitations Profile score at 20 weeks.
Secondary outcomes measuring muscle function (timed up and go), self-reported physical and psychosocial function (Functional Limitations Profile), and daily activity (accelerometry) also showed no improvement with vitamin D supplementation. Paradoxically, there was a small, but significant worsening in disease-specific quality of life (Minnesota score) in the treatment group compared with the placebo group. BNP level fell in the treatment group by 10 weeks compared with placebo. Secondary outcomes are shown in Table 3.
Table 5 shows that the intervention was well tolerated, with similar rates of cardiovascular and noncardiovascular adverse events in both arms of the trial. Five patients in the vitamin D2 arm had an increase in serum creatinine of >25% compared with baseline versus 1 patient in the placebo arm (P=0.11, Fisher exact test). No participant experienced an increase in creatinine of >50% from baseline. Hypercalcemia was mild and asymptomatic in all detected cases.
This study is the first to examine the effects of vitamin D on function and quality of life in typical older patients with heart failure. The study groups were representative of patients with heart failure in terms of their advanced age and poor exercise capacity, although women were slightly underrepresented. Levels of angiotensin-converting enzyme inhibitor, β-blocker, and spironolactone use are lower than in younger patients but are consistent with levels found in older patients with heart failure in clinical practice.24
The main finding is that 100 000 U of vitamin D2 given at baseline and 10 weeks did not improve physical function as measured by the 6-minute walk or timed up and go tests despite an increase of >100% (20 nmol/L, 12 ng/mL) in 25-hydroxyvitamin D levels at 10 weeks, which was sustained at 20 weeks. The minimum clinically important difference for the 6-minute walk distance is 30 m, and the narrow CIs surrounding the change make it highly unlikely that we missed a clinically significant effect of this vitamin D dose on the 6-minute walk distance. The lack of change in the Functional Limitations Profile measure (a subjective measure of physical and psychosocial function) reinforces these findings.
A small, but significant worsening of disease-specific quality of life was noted at 20 weeks in the treatment group. The significance of this finding is unclear, as is any potential explanatory mechanism. Conversely, daily activity increased nonsignificantly in the treatment group; thus, it is possible that these findings are due to chance. Blood pressure fell nonsignificantly at 10 weeks in the treatment group compared with placebo, but the change was not sustained at 20 weeks. No significant changes in tumor necrosis factor-α, renin, or aldosterone levels were seen; in particular, there was no evidence that vitamin D supplementation suppressed renin levels, as has been seen in animal studies. Interestingly, BNP was substantially reduced in the vitamin D arm compared with placebo, suggesting that vitamin D produced effects on the cardiovascular system. The observed fall in BNP levels is potentially clinically relevant, being similar to that previously observed with angiotensin-converting enzyme inhibitors and with spironolactone.25,26 We did not measure cardiac chamber sizes or ejection fraction in this study; thus, it is not clear whether this reduction in BNP indicates cardiac remodeling, a reduction in afterload from falling arterial blood pressure, or an effect on myocardial ischemia, but our findings suggest that vitamin D could still have a clinically important effect on the hemodynamic status of patients with heart failure even in the absence of a beneficial effect on exercise capacity. Similar findings have been seen previously when using spironolactone in patients with mild heart failure.27 Further imaging studies (eg, using cardiac MRI) would shed light on this interesting observation.
Since commencing this study, Schleithoff et al7 published a randomized controlled trial examining vitamin D supplementation in younger patients with heart failure. They showed that vitamin D3 supplementation at a dose of 2000 IU per day reduced tumor necrosis factor-α levels and increased interleukin-10 levels. There was no effect seen on BNP levels, left ventricular ejection fraction, blood pressure, or maximal oxygen uptake, which concurs with our finding that vitamin D did not improve exercise capacity. It is unclear why tumor necrosis factor-α was suppressed in this study but not in our study, but it is possible that the large burden of comorbid disease in our study provided alternative sources of chronic inflammation, which were not amenable to suppression with vitamin D. Supplementation with calcium in Schleithoff’s study also may play a role in explaining differences as it has been postulated to have beneficial or detrimental effects on vascular health independent of vitamin D supplementation.28
Strengths and Weaknesses
The tight CIs around the primary outcome are a major strength of the study because they allow us to exclude a clinically significant effect on physical function with considerable certainty. The final evaluable sample size reached the required target courtesy of a lower-than-predicted dropout rate, despite a lower-than-anticipated recruitment rate. Large, intermittent doses of vitamin D ensured that adherence to therapy was 100%, and the enrollment of typical older, frail patients with heart failure means that the results should be generalizable to a significant proportion of patients with left ventricular systolic dysfunction heart failure but may not be generalizable to the 50% of patients with heart failure with preserved systolic function.
Weaknesses include the fact that we used vitamin D2 because it was the only high-dose oral preparation available in the United Kingdom at the time of planning. Vitamin D3 would be preferable because it is thought to provide greater peak levels of vitamin D and has a longer half-life.29 It is also possible that a longer time period is necessary to elicit changes in physical function; however, other commonly used interventions (eg, angiotensin-converting enzyme inhibitors) produce improvements in exercise capacity within a few weeks.23
It is possible that daily dosing or larger doses of vitamin D may be required to influence the pathophysiology of heart failure to a degree that improves symptoms and exercise capacity. It is also possible that intervening earlier in the course of the disease process may pay dividends. Vitamin D has been postulated to have antihypertensive effects,30 and if the benefits seen in improving endothelial function11 translate to improvements in coronary artery disease, vitamin D may be able to ameliorate the antecedents of heart failure if given earlier in life. These areas merit further study.
We did not measure cardiac chamber sizes, ejection fraction, or hemodynamic variables because the primary focus of the study was on exercise capacity and quality of life. As a result, we are unable to determine any effect of vitamin D therapy on these variables.
In conclusion, 100 000 U of vitamin D2 taken every 10 weeks does not improve physical function or quality of life in older patients with heart failure.
We thank the staff of Royal Victoria Hospital, Dundee, for recruitment and outcomes facilities. We also thank Liz Furrie, Lesley MacFarlane, Gwen Kennedy, Tanya Sukhodub, and Heather Stevenson for laboratory assistance and performing the assays.
Sources of Funding
This study was supported by CSO grant CZB/4/300, a Chief Scientist Office, the Scottish Government, and NHS Education Scotland/CSO Clinician Scientist Award (to Dr Witham).
Dr Witham has received grant funding for vitamin D research from the Scottish Government, Diabetes UK, Chest Heart and Stroke Scotland, Heart Research UK, and the ME Society. Dr Struthers has received grant funding for vitamin D research from the Scottish Government, Diabetes UK, and Chest Heart and Stroke Scotland. Dr McMurdo has received grant funding for vitamin D research from the Scottish Government.
- ↵Cowie MR, Wood DA, Coats AJ, Thompson SG, Poole-Wilson PA, Suresh V, Sutton GC. Incidence and aetiology of heart failure; a population-based study. Eur Heart J. 1999; 20: 421–428.
- ↵Gott M, Barnes S, Parker C, Payne S, Seamark D, Gariballa S, Small N. Predictors of the quality of life of older people with heart failure recruited from primary care. Age Ageing. 2006; 35: 172–177.
- ↵Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R. Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr. 2006; 83: 754–759.
- ↵Dhesi JK, Jackson SH, Bearne LM, Moniz C, Hurley MV, Swift CG, Allain TJ. Vitamin D supplementation improves neuromuscular function in older people who fall. Age Ageing. 2004; 33: 589–595.
- ↵Trivedi DP, Doll R, Khaw KT. Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ. 2003; 326: 469–475.
- ↵Guyatt GH, Sullivan MJ, Thompson PJ, Fallen EL, Pugsley SO, Taylor DW, Berman LB. The 6-minute walk: a new measure of exercise capacity in patients with chronic heart failure. Can Med Assoc J. 1985; 132: 919–923.
- ↵O'Keeffe ST, Lye M, Donnellan C, Carmichael DN. Reproducibility and responsiveness of quality of life assessment and six minute walk test in elderly heart failure patients. Heart. 1998; 80: 377–382.
- ↵Bischoff HA, Stahelin HB, Monsch AU, Iversen MD, Weyh A, von Dechend M, Akos R, Conzelmann M, Dick W, Theiler R. Identifying a cut-off point for normal mobility: a comparison of the timed ‘up and go’ test in community-dwelling and institutionalised elderly women. Age Ageing. 2003; 32: 315–320.
- ↵Rector TS, Kubo SH, Cohn JN. Patients’ self-assessment of their congestive heart failure: content, reliability and validity of a new measure—the Minnesota Living With Heart Failure questionnaire. Heart Fail. 1987; 3: 198–209.
- ↵Hollis BW. Comparison of commercially available (125)I-based RIA methods for the determination of circulating 25-hydroxyvitamin D. Clin Chem. 2000; 46: 1657–1661.
- ↵Hutcheon SD, Gillespie ND, Crombie IK, Struthers AD, McMurdo ME. Perindopril improves six minute walking distance in older patients with left ventricular systolic dysfunction: a randomised double blind placebo controlled trial. Heart. 2002; 88: 373–377.
- ↵Witham MD, Gillespie ND, Struthers AD. Age is not a significant risk factor for failed trial of beta-blocker therapy in older patients with chronic heart failure. Age Ageing. 2004; 33: 467–472.
- ↵Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, Ohnishi M, Sawaki M, Fujii M, Matsumoto T, Matsui T, Kinoshita M. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol. 2001; 37: 1228–1233.
- ↵Macdonald JE, Kennedy N, Struthers AD. Effects of spironolactone on endothelial function, vascular angiotensin converting enzyme activity, and other prognostic markers in patients with mild heart failure already taking optimal treatment. Heart. 2004; 90: 765–770.
- ↵Sabbagh Z, Vatanparast H. Is calcium supplementation a risk factor for cardiovascular diseases in older women? Nutr Rev. 2009; 67: 105–108.
Low vitamin D levels are common in several cardiovascular diseases, including heart failure, and have been implicated in endothelial dysfunction, immune dysregulation, and skeletal myopathy, all key pathophysiological processes in heart failure. Results from this randomized controlled trial show that in older patients with heart failure with low baseline 25-hydroxyvitamin D levels, high-dose oral vitamin D did not improve exercise capacity or quality of life, despite significantly increasing circulating 25-hydroxyvitamin D levels. These results do not support a role for vitamin D supplementation in older patients with heart failure, even when circulating 25-hydroxyvitamin D levels are low.