Longitudinal High-Sensitivity C-Reactive Protein and Longer-Term Cardiovascular Outcomes in Optimally-Treated Patients With High-Risk Vascular Disease.

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, p <0.0001 for patients with and without MACE, respectively) and showed an upward trajectory during follow-up, whereas median hsCRP levels remained <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], p <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 remain <2 mg/L.

HbA1c, Coronary atheroma progression and cardiovascular outcomes.

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 < 0.001]. On-treatment HbA1c levels were independently associated with MACE [hazard ratio (95% confidence interval): 1.13(1.04, 1.23), p = 0.005]. CONCLUSIONS: Independent of achieved cardiovascular risk factor control, greater HbA1c levels significantly associate with coronary atheroma progression rates and clinical outcomes. These results support the notion of a direct, specific effect of glycemic control upon coronary atheroma and atherosclerotic events, supporting the rationale of therapies designed to directly modulate it.

Oral Calcium Supplements Associate With Serial Coronary Calcification: Insights From Intravascular Ultrasound.

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 < 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). 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.

Progression of coronary atherosclerosis in patients without standard modifiable risk factors.

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 â€‹= â€‹165) and with (n â€‹= â€‹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 â€‹± â€‹12 vs. 129 â€‹± â€‹17 â€‹mmHg, p â€‹< â€‹0.001), low-density lipoprotein cholesterol (87 â€‹± â€‹21 vs. 104 â€‹± â€‹34 â€‹mg/dl, p â€‹< â€‹0.001), triglycerides [106 vs. 136 â€‹mg/dl, p â€‹< â€‹0.001)] and C-reactive protein [1.5 vs. 2.1 â€‹mg/l, p â€‹= â€‹0.001]. At baseline, patients without modifiable risk factors had a lower percent atheroma volume (35.7 â€‹± â€‹8.6 vs. 38 â€‹± â€‹8.8%, p â€‹= â€‹0.004) and total atheroma volume (174.7 â€‹± â€‹80 vs. 190.9 â€‹± â€‹84 â€‹mm3, p â€‹= â€‹0.03) and less images with calcification (22.2 vs. 26.5%, p â€‹= â€‹0.025). The use of aspirin and statin prior to and during the trials was similar. The use of ACE inhibitors and beta blockers was lower in the no risk factor group prior to and during the trials. The change in percent atheroma volume (-0.2 â€‹± â€‹2.8 vs. -0.1 â€‹± â€‹3.6%, p â€‹= â€‹0.71), total atheroma volume (-5.5 â€‹± â€‹23.4 vs. -3.8 â€‹± â€‹22.7 â€‹mm3, p â€‹= â€‹0.42), and the percentage of patients demonstrating any degree of progression (50.9% vs 45.1%, p â€‹= â€‹0.20) were similar in those without and with standard modifiable risk factors, respectively. CONCLUSION: Patients who develop clinical coronary atherosclerosis without standard modifiable risk factors have similar rates of plaque progression to those with traditional risk factors.