How Follow-Up Period in Prospective Cohort Studies Affects Relationship Between Baseline Serum 25(OH)D Concentration and Risk of Stroke and Major Cardiovascular Events

Abstract

Background/Objectives: Prospective cohort studies are useful for studying how biomolecular status affects risk of adverse health outcomes. Less well known is that the longer the follow-up time, the lower the association (or "apparent effect") due to "regression dilution". Here, we evaluate how follow-up interval from baseline to "event" affects the relationship between baseline serum 25-hydroxyvitamin D [25(OH)D] concentration and the later incidence of stroke and major cardiovascular events (MACEs). Methods: Findings for the relative risk (RR) of stroke and MACEs with respect to serum 25(OH)D concentrations at baseline from prospective cohort studies were plotted against mean follow-up time. Fifteen studies from mainly European countries and the United States were used for stroke and nine studies for MACEs. Linear regression analyses were used to study data for follow-up periods of up to 10 years and for more than 10 years. Results: For stroke, the linear regression fit for 1-10 years is RR = 0.34 + (0.065 × follow-up [years]), r = 0.84, adjusted r² = 0.67, p < 0.001. No significant variations in association were found for studies with follow-up periods of 10-20 years. For MACEs, the linear fit for 1-8.1 years is RR = 0.61 + (0.055 × follow-up [years]), r = 0.81, adjusted r² = 0.59, p = 0.03. Discussion: The shorter the follow-up period, the greater the apparent effect of better vitamin D status in reducing risk of stroke and MACEs. In addition, the apparent effect of higher 25(OH)D concentration found for the shortest follow-up time is more than twice as great as the estimate based on average follow-up intervals for all studies. Mechanisms have been found to explain how higher serum 25(OH)D concentrations could reduce risk of stroke and MACEs. Randomized controlled trials have not shown that vitamin D supplementation significantly reduces risk of either stroke or MACEs, probably because risk of both outcomes increases rapidly below 15 ng/mL (38 nmol/L) and it is difficult in Western developed countries to enroll enough participants with concentrations that low. Nonetheless, vitamin D's role in reducing risk of stroke and MACEs could be considered causal on the basis of an evaluation of the evidence using Hill's criteria for causality in a biological system. Conclusions: Serum 25(OH)D concentrations above 20 ng/mL are associated with significantly reduced risk of stroke and MACEs prospectively and in an apparent causal manner. Raising serum 25(OH)D concentrations to >20 ng/mL should, therefore, be recommended for everyone likely to be at risk for stroke or MACEs and indeed in the general population.

Keywords: cardiovascular disease; causality; follow-up period/time; heart failure; hemorrhagic; hypertension; ischemic; prospective cohort study; stroke; vitamin D.

Figure 1

Plot of relative risk for stroke versus years of follow-up with respect to high vs. low 25(OH)D concentration, with regression fits to studies of less than 10 years and for those carried out over more than 10 years; 95% CI, 95% confidence interval. Equation for regression fit to RR for follow-up period < 10 years is RR = 0.34 + (0.065 × follow-up [years]), r = 0.84, adjusted r² = 0.67, p < 0.001.

Figure 2

Plot of relative risk of a major cardiovascular event (MACE) versus mean follow-up period for high versus low 25(OH)D concentration. Equation for regression fitted to RRs over follow-up periods <10 years is RR = 0.61 + (0.055 × follow-up [years]), r = 0.81, adjusted r² = 0.59, p = 0.03.