Impact of high-dose statins on vitamin D levels and platelet function in patients with coronary artery disease.

BACKGROUND: Statins represent a pivotal treatment in coronary artery disease, offering a reduction in cardiovascular risk even beyond their lipid-lowering action. However, the mechanism of these "pleiotropic" benefits of statins is poorly understood. Vitamin D has been suggested as a potential mediator of the anti-inflammatory, anti-thrombotic and vascular protecting effects of statins. Aim of present study was to assess the impact of a high-intensity statin therapy on vitamin D levels and platelet function in patients with coronary artery disease. METHODS: Patients discharged on dual antiplatelet therapy and high-intensity statins after an ACS or elective PCI were scheduled for main chemistry and vitamin D levels assessment at 30-90days post-discharge. Vitamin D (25-OHD) dosing was performed by chemiluminescence method through the LIAISON® Vitamin D assay (Diasorin Inc). Platelet function was assessed by Multiplate® (multiple platelet function analyser; Roche Diagnostics AG). RESULTS: Among 246 patients included, 142 were discharged on a new statin therapy or with an increase in previous dose (Inc-S), while 104 were already receiving a high-dose statin at admission, that remained unchanged (Eq-S). Median follow-up was 75.5days. Patients in the Inc-S group were younger (p=0.01), smokers (p<0.001), with a less frequent history of hypercholesterolemia (p=0.05), diabetes (p=0.03), hypertension (p=0.02), or previous cardiovascular events (p<0.001). They were more often admitted for an acute coronary syndrome (p<0.001) and used less anti-hypertensive drugs or nitrates. Higher total circulating calcium was observed in the Inc-S group (p=0.004), while baseline vitamin D levels were similar in the 2 groups (p=0.30). A significant reduction in the circulating low-density lipoprotein (LDL) cholesterol was observed in the Inc-S group. Vitamin D levels increased in the Inc-S patients but not in the Eq-S group (delta-25OHD: 23.2±20.5% vs 3.1±4.7%, p=0.003), with a linear relationship between the magnitude of vitamin D elevation and the reduction of LDL cholesterol (r=-0.17, p=0.01). Platelet reactivity was significantly lower in the Inc-S patients, when evaluating aggregation with different platelet activating stimuli (arachidonic acid, p=0.02, collagen, p=0.004, thrombin-activating peptide, p=0.07, ADP, p=0.002). CONCLUSIONS: In patients with coronary artery disease, the addition of a high-intensity statin treatment, besides the lipid-lowering effects, is associated to a significant increase in vitamin D levels and lower platelet reactivity, potentially providing explanation of the "pleiotropic" benefits of statins therapy in cardiovascular disease.

Vitamin D levels and high-residual platelet reactivity in patients receiving dual antiplatelet therapy with clopidogrel or ticagrelor.

BACKGROUND: Suboptimal platelet inhibition still represents an important challenge, especially for patients undergoing percutaneous coronary interventions (PCIs). However, very few are known so far on the predictors of high-residual platelet reactivity (HRPR) despite antiplatelet strategies. Increasing attention has been paid in the last years to the role of vitamin D in atherothrombosis. Therefore, the aim of our study was to evaluate the impact of vitamin D levels on platelet function in patients treated with dual antiplatelet therapy (DAPT). Patients treated with DAPT (ASA and clopidogrel or ticagrelor) after a recent acute coronary syndrome (ACS) or elective PCI were scheduled for platelet function assessment at 30-90 days post-discharge. Platelet function was assessed by whole blood impedance aggregometry (Multiplate®-Roche Diagnostics AG), HRPR was considered for ASPI test values > 862 AU*min (for ASA) and adenosine diphosphate (ADP) test values ≥417 AU*min (for ADP-antagonists). Fasting samples were obtained for main chemistry parameters and vitamin D level assessment. Our population is represented by 503 patients, who were divided according to vitamin D quartiles (≤9.1; 9.2-14.4; 14.5-21.7; >21.7 ng/ml). Lower vitamin D levels related with age (p = 0.04), diabetic status (p = 0.05), and previous coronary surgery (p = 0.007), therapy with beta-blockers and statins (p = 0.01 and p = 0.02). Vitamin D inversely related to the levels of total cholesterol (p = 0.01), triglycerides (p < 0.001), hemoglobin (p = 0.05), and HbA1c (p < 0.001). Significantly higher platelet reactivity was observed after platelet stimulation with ADP (p = 0.01), but not with other platelet activators. The prevalence of HRPR for ASA was low (1.2%) and not conditioned by Vitamin D levels (adjusted OR[95%CI] = 1.56[0.71-3.5], p = 0.27). HRPR with ADP-antagonists was observed in 26% of patients, and the rate increased with lower vitamin D quartiles (37.3% vs 22.2% vs 24.4% vs 20.2%, p = 0.005, adjusted OR[95%CI] = 1.23[1.02-1.49], p = 0.04). An absolute increase in HRPR with lower vitamin D levels was similarly observed among patients receiving ticagrelor (adjusted OR[95% CI] = 1.40[0.95-2.06], p = 0.08), and those on clopidogrel (adjusted OR[95%CI] = 1.31[0.99-1.75], p = 0.06). Thus, lower vitamin D levels are associated with higher platelet reactivity and impaired effectiveness of ADP-antagonists, while not influencing the effectiveness of ASA. Future studies will tell whether vitamin D supplementation can reduce platelet reactivity, overcoming the phenomenon of resistance to antiplatelet agents.

Vitamin D deficiency is independently associated with the extent of coronary artery disease.

BACKGROUND: Vitamin D (25-OH D3) deficiency represents a rising social and economic problem in Western countries. Vitamin D has been recently reported to modulate inflammatory processes, endothelium and smooth muscle cell proliferation and even platelet function, thus potentially modulating atherothrombosis. Great interest has been addressed on its impact on cardiovascular outcome, with contrasting results. The aim of current study was to evaluate the relationship between 25-OH D3 and the extent of coronary artery disease (CAD) in a consecutive cohort of patients undergoing coronary angiography. MATERIALS AND METHODS: Patients undergoing elective coronary angiography were included in a cross-sectional study. Fasting samples were collected for 25-OH D3 levels assessment. Significant CAD was defined as at least 1 vessel stenosis > 50%, while severe CAD as left main and/or trivessel disease, as evaluated by quantitative coronary angiography. RESULTS: Hypovitaminosis D was observed in 70·4% of 1484 patients. Patients were divided according to vitamin D tertiles (< 9·6; 9·6-18·4; ≥ 18·4). Lower vitamin D levels were associated with age, female gender (P < 0·001), renal failure (P = 0·05), active smoking (P = 0·001), acute coronary syndrome at presentation (P < 0·001), therapy with calcium antagonists (P = 0·02) and diuretics (P < 0·001), less beta-blockers (P = 0·02) and statins (P = 0·001) use. Vitamin D was directly related to haemoglobin (P < 0·001) and inversely with platelet count (P = 0·002), total and low-density-lipoprotein cholesterol (P = 0·002 and P < 0·001) and triglycerides (P = 0·01). Vitamin D did not influence angiographic features of coronary lesions, but was associated with higher prevalence of left main or right CAD (P = 0·03). Vitamin D deficiency was significantly associated with higher prevalence of CAD (adjusted OR [95%CI] = 1·32[1·1-1·6], P = 0·004) and severe CAD (adjusted OR [95%CI] = 1·18[1-1·39], P = 0·05). CONCLUSION: Hypovitaminosis D was observed in the vast majority of patients undergoing coronary angiography. Vitamin D deficiency is significantly associated with the prevalence and extent of CAD, especially for patients with values < 10 ng/mL. Therefore, future large studies are needed to evaluate whether vitamin D supplementation may prevent CAD and its progression.