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The relation between serial high-sensitivity C-reactive protein (hsCRP) and long-term major cardiovascular events (MACEs; cardiovascular death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) has not been explored in optimally-treated patients with atherosclerotic cardiovascular disease. We tested the hypothesis that longitudinal follow-up hsCRP (repeated measures over time) would associate with 30-month MACE rates. We performed a post hoc analysis of ACCELERATE (Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibitor with Evacetrapib in Patients with High-Risk for Vascular Outcomes), involving optimally-treated patients with high-risk vascular disease, with available baseline and at least 1 follow-up hsCRP level. Using multivariable Cox proportional hazard models, we determined the association of longitudinal follow-up hsCRP with MACE at 30 months among 8,563 patients (aged 64.6 ± 9 years, 22% women). Patients with incident MACE (n = 961) had higher baseline hsCRP levels (1.77 vs 1.46 mg/L, plt;0.0001 for patients with and without MACE, respectively) and showed an upward trajectory during follow-up, whereas median hsCRP levels remainedlt;2 mg/L at all time points (1.83 vs 1.53 mg/L, 1.91 vs 1.53 mg/L, 1.76 vs 1.37 mg/L, at 3, 12, and 24 months, respectively). In a multivariable analysis, higher longitudinal hsCRP levels were independently associated with MACE (hazard ratio [95% confidence interval] per SD 1.19 [1.10 to 1.29], plt;0.001), the majority of its individual components and all-cause death. Multivariable models containing longitudinal hsCRP provided improved predictive ability of MACE over baseline hsCRP. In the setting of established medical therapies, longitudinal follow-up hsCRP was independently associated with long-term MACE. In conclusion, these findings suggest that longitudinal hsCRP represents a novel approach of residual cardiovascular risk even when on-treatment hsCRP levels remainlt;2 mg/L.

Objectives This study sought to evaluate and assess the extent of serial coronary artery calcification in response to oral calcium supplementation. Background Oral calcium supplements are frequently used despite their cardiovascular safety remaining controversial. Their effects on serial coronary calcification are not well established. Methods In a post hoc patient-level analysis of 9 prospective randomized trials using serial coronary intravascular ultrasound, changes in serial percentage of atheroma volume (PAV) and calcium indices (CaI) were compared in matched segments of patients coronary artery disease who were receiving concomitant calcium supplements (n = 447) and in those who did not receive supplements (n = 4,700) during an 18- to 24-month trial period. Results Patients (mean age 58 ± 9 years; 73% were men; 43% received concomitant high-intensity statins) demonstrated overall annualized changes in PAV and CaI with a mean of −0.02 ± 1.9% (p = 0.44) and a median of 0.02 (interquartile range: 0.00 to 0.06) (p Conclusions Oral calcium supplementation may increase calcium deposition in the coronary vasculature independent of changes in atheroma volume. The impact of these changes on plaque stability and cardiovascular outcomes requires further investigation.

Background and aims: We tested the hypothesis that on-treatment HbA1c levels independently associate with coronary atheroma progression and major adverse cardiovascular events (MACE: death, myocardial infarction, cerebrovascular accident, coronary revascularization, or hospitalization for unstable angina) rates. Methods: We performed a post-hoc pooled analysis of data from seven prospective, randomized trials involving serial coronary intravascular ultrasonography (IVUS). The percent atheroma volume (PAV) was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque. Using multivariable mixed modeling, we determined the association of on-treatment HbA1c with annualized change in PAV. Cox proportional hazard models were used to assess the association of HbA1c with incidence of MACE. Results: Among 3,312 patients (mean age 58.6±9years, 28.4%women) average on-treatment HbA1c was 6.2±1.1%. Overall, there was no net significant annualized change in PAV (0.12±0.19%, p = 0.52). In a fully adjusted multivariable analysis (following adjustment of age, sex, body mass index, systolic blood pressure, smoking, low- and high-density lipoprotein cholesterol, triglyceride levels, peripheral vascular disease, trial, region, and baseline PAV), higher on-treatment HbA1c levels were independently associated with annualized changes in PAV [beta-estimate (95% confidence interval): 0.13(0.08, 0.19), p

Background Hemoglobin A1c (HbA1c) reflects long-term glycemic control and is associated with an increased risk of cardiovascular events among diabetic and non-diabetic patients. The specific impact of HbA1c upon atheroma progression and incident cardiovascular events relative to the presence of other cardiovascular risk factors remains uncertain. Purpose We tested the hypothesis that on-treatment HbA1c levels independently associate with coronary atheroma progression measured with serial intravascular ultrasonography (IVUS) and major adverse cardiovascular events (MACE: death, myocardial infarction, cerebrovascular accident, coronary revascularization, or hospitalization for unstable angina) rates. Methods We performed a post-hoc pooled analysis of data from eight prospective, randomized trials involving serial coronary IVUS. HbA1c was measured at baseline and the average of the follow-up values was taken. The percent atheroma volume (PAV) was calculated as the proportion of the entire vessel wall occupied by atherosclerotic plaque, throughout the segment of interest. Using multivariable mixed modeling, we determined the association of HbA1c with annualized change in PAV. Cox proportional hazard models were used to assess the association of HbA1c with incidence of MACE. Results Among 2,791 patients, mean age was 58.9±9 years and 29.1% were women. Mean on-treatment low-density lipoprotein (LDL)-cholesterol was 80.2±33.7 mg/dl and median on-treatment triglycerides (TG) were 125.5 (94.7, 170.2) mg/dl. Mean baseline and follow-up HbA1c was 6.2±1.2% and 6.3±1.2%, respectively. Overall, there was no net significant annualized change in PAV (0.15±0.21, p=0.47). In a fully adjusted multivariable analysis (following adjustment of age, sex, body mass index (BMI), systolic blood pressure, smoking, LDL- and high-density lipoprotein cholesterol, TG levels, peripheral artery disease, trial, region, and baseline PAV), higher on-treatment HbA1c levels were independently associated with annualized changes in PAV [beta-estimate (95% confidence interval): 0.13 (0.07, 0.19), p Conclusions Independent of achieved cholesterol levels, vascular risk factors and BMI, greater HbA1c levels significantly associate with coronary atheroma progression and clinical outcomes. These results support the notion of a direct, specific effect of glycemic control upon the natural history of coronary atheroma and atherosclerotic events, supporting the rationale of therapies designed to directly modulate it. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Iryna Dykun was supported by the German Research Foundation

Background High-sensitivity C-reactive protein (hsCRP) predicts major cardiovascular events (MACE) in patients with chronic atherosclerotic cardiovascular disease. The relationship between serial longitudinal hsCRP assessment and long-term MACE has not been explored. Purpose We tested the hypothesis that longitudinal follow-up hsCRP levels (repeated measures over time) would associate with 30-month MACE (cardiovascular death, myocardial infarction, cerebrovascular accident, coronary revascularization or hospitalization for unstable angina) rates. Methods We performed a post-hoc analysis of the ACCELERATE trial of optimally-treated patients with high-risk vascular disease and evaluated data from patients with available baseline and at least one follow-up hsCRP level measured at 3, 12, and 24 months. Those with a MACE event occurring before 3 months were omitted. Using multivariable Cox proportional hazard models, we determined the association of longitudinal follow-up hsCRP levels with MACE, its components, and all-cause mortality at 30-months, adjusting for age, race, sex, region, smoking status, body mass index, diabetes, baseline hsCRP, low density lipoprotein-cholesterol, high-density lipoprotein cholesterol, systolic blood pressure, statin use, and treatment group. Results Among 8,563 patients, mean age was 64.6±9.3 years and 22.2% were women. Median baseline hsCRP was 1.49 (0.74, 3.3) mg/L. Median time-weighted average follow-up hsCRP was 1.80 (0.88, 3.9) mg/L and mean time-weighted average follow-up LDL-C was 71.7±28.0 mg/dL. At 30 months, there was a significant stepwise relationship between cumulative MACE and increasing tertiles of last prior hsCRP value before an event or censoring (KM estimates for tertiles 1–3, respectively: 8.9 vs. 12.4 vs. 15.6%, p Conclusions In the setting of established medical therapies, longitudinal follow-up hsCRP is significantly associated with an increased risk of long-term MACE, myocardial infarction, stroke, cardiovascular mortality, coronary revascularization, and all-cause death. Longitudinal follow-up hsCRP may thus represent a novel marker of residual cardiovascular risk, supporting further work exploring the potential diagnostic and therapeutic implications of these findings. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Iryna Dykun was supported by the German Research Foundation

Background and aims The outcome of patients with clinical coronary artery disease despite traditional risk factors is poorly understood. Methods Clinical characteristics and plaque burden on serial intravascular ultrasonography were compared in patients without (n ​= ​165) and with (n ​= ​492) standard modifiable risk factors after matching on age, sex and use of statins from a database of 5823 patients participating in clinical trials of anti-atherosclerotic therapies. Results Patients without standard modifiable risk factors had lower baseline systolic blood pressure (118 ​± ​12 vs. 129 ​± ​17 ​mmHg, p ​, Highlights • Outcome of patients with CAD despite no traditional risk factors is poorly understood. • Serial intravascular ultrasound studies provide an opportunity to examine this. • Patients without standard risk factors had lower plaque burden and calcification. • Use of aspirin and statin was similar in patients with and without standard risk factors. • Plaque progression was similar in those without and with standard risk factors.

This study sought to evaluate and assess the extent of serial coronary artery calcification in response to oral calcium supplementation.Oral calcium supplements are frequently used despite their cardiovascular safety remaining controversial. Their effects on serial coronary calcification are not well established.In a post hoc patient-level analysis of 9 prospective randomized trials using serial coronary intravascular ultrasound, changes in serial percentage of atheroma volume (PAV) and calcium indices (CaI) were compared in matched segments of patients coronary artery disease who were receiving concomitant calcium supplements (n = 447) and in those who did not receive supplements (n = 4,700) during an 18- to 24-month trial period.Patients (mean age 58 ± 9 years; 73% were men; 43% received concomitant high-intensity statins) demonstrated overall annualized changes in PAV and CaI with a mean of -0.02 ± 1.9% (p = 0.44) and a median of 0.02 (interquartile range: 0.00 to 0.06) (p 0.001) from baseline, respectively. Following propensity-weighted mixed modeling adjusting for treatment and a range of demographic, clinical, ultrasonic, and laboratory parameters (including but not limited to sex, race, baseline, and annualized change in PAV, baseline CaI, concomitant high-intensity statins, diabetes mellitus, renal function), there were no significant between-group differences in annualized changes in PAV (least-squares mean: 0.09; 95% confidence interval [CI]: -0.20 to 0.37 vs. 0.01; 95% CI: -0.27 to 0.29; p = 0.092) according to calcium supplement intake. Per a multivariable logistic regression model accounting for the range of covariates described, calcium supplementation independently associated with an increase in annualized CaI (odds ratio: 1.15; 95% CI: 1.05 to 1.26; p = 0.004).Oral calcium supplementation may increase calcium deposition in the coronary vasculature independent of changes in atheroma volume. The impact of these changes on plaque stability and cardiovascular outcomes requires further investigation.