Abstract Body (Do not enter title and authors here): Background: Many observational studies have reported associations between low 25-hydroxyvitamin D (25[OH] vit D) levels and adverse cardiovascular (CV) outcomes. Recent randomized clinical trials have not found vitamin (vit) D₃ supplementation to reduce CV risk. However, these trials gave “blanket” doses regardless of 25[OH] vit D level, with none having "treated to target". We performed the first study where subjects were prescribed vit D₃ supplementation with ongoing titration based on individual 25[OH] vit D levels.
Methods: Target-D (NCT: 02996721) is a randomized clinical trial designed to determine if achieving 25[OH] vit D levels >40 ng/mL among acute coronary syndrome (ACS) patients resulted in a reduction of adverse CV events. Subjects meeting study criteria from Apr 2017 to May 2023 (average follow-up 4.2±2.0 years) were randomized to receive usual of care or clinical management of 25[OH] vit D. The treatment arm received targeted vit D₃ supplementation and ongoing titration based on a dosing algorithm to reach and maintain a target 25[OH] vit D level of >40 ng/mL. Target-D concluded follow-up on Mar 17, 2025, when >104 primary outcome events (MACE: composite of death, MI, heart failure (HF) hospitalization, and stroke) occurred.
Results: The study consort diagram is shown in Figure 1. Age averaged 62.6±11.4 years, 78.1% were male, and 76.0% presented with an MI. Baseline 25[OH] vit D levels were 26.8±12.7 ng/mL (median: 25), with 87.0% 25[OH] vit D levels <40 ng/mL. Among those randomized to the treatment arm with a 25[OH] vit D levels <40, 58.8% of patients began vit D₃ dosing at 5000 IU. The number of events over the study period are shown in Figure 2. While the primary endpoint of MACE did not achieve significance in the intention-to-treat (ITT) analysis (Figure 3), its component of follow-up MI was significantly reduced in the vit D arm (7.9% vs. 3.8%, log-rank p=0.03). In the per-protocol (PP) analyses, though not statistically significant, there were clinically relevant risk reductions for MACE, death, and MI when achieving and maintaining 25[OH] vit D levels >40 ng/mL.
Conclusions: Average baseline 25[OH] vit D levels were deficient in >85% of participants. The primary endpoint of MACE did not achieve statistical significance in the ITT analysis; however, follow-up MI was reduced by over half in the vit D arm. The PP analyses showed clinically relevant risk reductions for MACE, death, and MI when 25[OH] vit D levels >40 ng/mL were achieved.