A randomized controlled trial of genetic testing and cascade screening in familial hypercholesterolemia.

PURPOSE: Family-based cascade screening from index probands is considered an effective way of identifying undiagnosed individuals with familial hypercholesterolemia (FH). The role of genetic testing of the proband in the success of cascade screening for FH is unknown. METHODS: We randomized 240 individuals with a clinical diagnosis of FH to genetic testing for FH (n = 160) or usual care with lipid testing alone (n = 80). The primary study endpoint was the proportion of probands with at least one relative enrolled in the study within one year after the notification of results. RESULTS: Proband median age was 59 (47-67) and 71% were female. Only 28 (12%) probands succeeded in enrolling a relative. While the genetic testing group had a higher proportion of probands with relatives enrolled (13.1%) compared with the usual care group (8.8%), this difference was not significant (p = 0.40). In subgroup analyses, enrollment of a relative was higher in the pathogenic variant group (22.7%) compared to the no pathogenic variant (9.5%) and usual care groups (8.8%) (p = 0.04). CONCLUSION: We observed a low rate of family participation in cascade screening despite repeated recommendations to probands. Compared to usual care, genetic testing did not improve family participation in cascade screening for FH. CLINICAL TRIAL NUMBER: NCT04526457.

Effects of vadadustat on hemoglobin concentrations in patients receiving hemodialysis previously treated with erythropoiesis-stimulating agents.

Background: Vadadustat, an inhibitor of hypoxia-inducible factor prolyl-4-hydroxylase domain dioxygenases, is an oral investigational agent in development for the treatment of anemia secondary to chronic kidney disease. Methods: In this open-label Phase 2 trial, vadadustat was evaluated in 94 subjects receiving hemodialysis, previously maintained on epoetin alfa. Subjects were sequentially assigned to one of three vadadustat dose cohorts by starting dose: 300 mg once daily (QD), 450 mg QD or 450 mg thrice weekly (TIW). The primary endpoint was mean hemoglobin (Hb) change from pre-baseline average to midtrial (Weeks 7-8) and end-of-trial (Weeks 15-16) and was analyzed using available data (no imputation). Results: Overall, 80, 73 and 68% of subjects in the 300 mg QD, 450 mg QD, and 450 mg TIW dose cohorts respectively, completed the study. For all dose cohorts no statistically significant mean change in Hb from pre-baseline average was observed, and mean Hb concentrations-analyzed using available data-remained stable at mid- and end-of-trial. There was one subject with an Hb excursion >13 g/dL. Overall, 83% of subjects experienced an adverse event (AE); the proportion of subjects who experienced at least one AE was similar among the three dose cohorts. The most frequently reported AEs were nausea (11.7%), diarrhea (10.6%) and vomiting (9.6%). No deaths occurred during the study. No serious AEs were attributed to vadadustat. Conclusions: Vadadustat maintained mean Hb concentrations in subjects on hemodialysis previously receiving epoetin. These data support further investigation of vadadustat to assess its long-term safety and efficacy in subjects on hemodialysis.

Clinical Trial of Vadadustat in Patients with Anemia Secondary to Stage 3 or 4 Chronic Kidney Disease.

BACKGROUND: Therapeutic options for the treatment of anemia secondary to chronic kidney disease (CKD) remain limited. Vadadustat (AKB-6548) is an oral hypoxia-inducible factor prolyl-hydroxylase domain (HIF-PHD) inhibitor that is being investigated for the treatment of anemia secondary to CKD. METHODS: A phase 2a, multicenter, randomized, double-blind, placebo-controlled, dose-ranging trial (NCT01381094) was undertaken in adults with anemia secondary to CKD stage 3 or 4. Eligible subjects were evenly randomized to 5 groups: 240, 370, 500, or 630 mg of once-daily oral vadadustat or placebo for 6 weeks. All subjects received low-dose supplemental oral iron (50 mg daily). The primary endpoint was the mean absolute change in hemoglobin (Hb) from baseline to the end of treatment. Secondary endpoints included iron indices, safety, and tolerability. RESULTS: Ninety-three subjects were randomized. Compared with placebo, vadadustat significantly increased Hb after 6 weeks in a dose-dependent manner (analysis of variance; p < 0.0001). Vadadustat increased the total iron-binding capacity and decreased concentrations of ferritin and hepcidin. The proportion of subjects with at least 1 treatment-emergent adverse event was similar between vadadustat- and placebo-treated groups. No significant changes in blood pressure, vascular endothelial growth factor, C-reactive protein, or total cholesterol were observed. Limitations of this study included its small sample size and short treatment duration. CONCLUSIONS: Vadadustat increased Hb levels and improved biomarkers of iron mobilization and utilization in patients with anemia secondary to stage 3 or 4 CKD. Global multicenter, randomized phase 3 trials are ongoing in non-dialysis-dependent and dialysis-dependent patients.

Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E.

Cholesteryl ester transfer protein (CETP) mediates the transfer of HDL cholesteryl esters for triglyceride (TG) in VLDL/LDL. CETP inhibition, with anacetrapib, increases HDL-cholesterol, reduces LDL-cholesterol, and lowers TG levels. This study describes the mechanisms responsible for TG lowering by examining the kinetics of VLDL-TG, apoC-II, apoC-III, and apoE. Mildly hypercholesterolemic subjects were randomized to either placebo (N = 10) or atorvastatin 20 mg/qd (N = 29) for 4 weeks (period 1) followed by 8 weeks of anacetrapib, 100 mg/qd (period 2). Following each period, subjects underwent stable isotope metabolic studies to determine the fractional catabolic rates (FCRs) and production rates (PRs) of VLDL-TG and plasma apoC-II, apoC-III, and apoE. Anacetrapib reduced the VLDL-TG pool on a statin background due to an increased VLDL-TG FCR (29%; P = 0.002). Despite an increased VLDL-TG FCR following anacetrapib monotherapy (41%; P = 0.11), the VLDL-TG pool was unchanged due to an increase in the VLDL-TG PR (39%; P = 0.014). apoC-II, apoC-III, and apoE pool sizes increased following anacetrapib; however, the mechanisms responsible for these changes differed by treatment group. Anacetrapib increased the VLDL-TG FCR by enhancing the lipolytic potential of VLDL, which lowered the VLDL-TG pool on atorvastatin background. There was no change in the VLDL-TG pool in subjects treated with anacetrapib monotherapy due to an accompanying increase in the VLDL-TG PR.

US physician practices for diagnosing familial hypercholesterolemia: data from the CASCADE-FH registry.

BACKGROUND: In the US familial hypercholesterolemia (FH), patients are underidentified, despite an estimated prevalence of 1:200 to 1:500. Criteria to identify FH patients include Simon Broome, Dutch Lipid Clinic Network (DLCN), or Make Early Diagnosis to Prevent Early Deaths (MEDPED). The use of these criteria in US clinical practices remains unclear. OBJECTIVE: To characterize the FH diagnostic criteria applied by US lipid specialists participating in the FH Foundation's CASCADE FH (CAscade SCreening for Awareness and DEtection of Familial Hypercholesterolemia) patient registry. METHODS: We performed an observational, cross-sectional analysis of diagnostic criteria chosen for each adult patient, both overall and by baseline patient characteristics, at 15 clinical sites that had contributed data to the registry as of September 8, 2015. A sample of 1867 FH adults was analyzed. The median age at FH diagnosis was 50 years, and the median pretreatment low-density lipoprotein cholesterol (LDL-C) value was 238 mg/dL. The main outcome was the diagnostic criteria chosen. Diagnostic criteria were divided into five nonexclusive categories: "clinical diagnosis," MEDPED, Simon Broome, DLCN, and other. RESULTS: Most adults enrolled in CASCADE FH (55.0%) received a "clinical diagnosis." The most commonly used formal criteria was Simon-Broome only (21%), followed by multiple diagnostic criteria (16%), MEDPED only (7%), DLCN only (1%), and other (0.5%), P < .0001. Of the patients with only a "clinical diagnosis," 93% would have met criteria for Simon Broome, DLCN, or MEDPED based on the data available in the registry. CONCLUSIONS: Our findings demonstrate heterogeneity in the application of FH diagnostic criteria in the United States. A nationwide consensus definition may lead to better identification, earlier treatment, and ultimately CHD prevention.

Treatment Gaps in Adults With Heterozygous Familial Hypercholesterolemia in the United States: Data From the CASCADE-FH Registry.

BACKGROUND: Cardiovascular disease burden and treatment patterns among patients with familial hypercholesterolemia (FH) in the United States remain poorly described. In 2013, the FH Foundation launched the Cascade Screening for Awareness and Detection (CASCADE) of FH Registry to address this knowledge gap. METHODS AND RESULTS: We conducted a cross-sectional analysis of 1295 adults with heterozygous FH enrolled in the CASCADE-FH Registry from 11 US lipid clinics. Median age at initiation of lipid-lowering therapy was 39 years, and median age at FH diagnosis was 47 years. Prevalent coronary heart disease was reported in 36% of patients, and 61% exhibited 1 or more modifiable risk factors. Median untreated low-density lipoprotein cholesterol (LDL-C) was 239 mg/dL. At enrollment, median LDL-C was 141 mg/dL; 42% of patients were taking high-intensity statin therapy and 45% received >1 LDL-lowering medication. Among FH patients receiving LDL-lowering medication(s), 25% achieved an LDL-C <100 mg/dL and 41% achieved a ≥50% LDL-C reduction. Factors associated with prevalent coronary heart disease included diabetes mellitus (adjusted odds ratio 1.74; 95% confidence interval 1.08-2.82) and hypertension (2.48; 1.92-3.21). Factors associated with a ≥50% LDL-C reduction from untreated levels included high-intensity statin use (7.33; 1.86-28.86) and use of >1 LDL-lowering medication (1.80; 1.34-2.41). CONCLUSIONS: FH patients in the CASCADE-FH Registry are diagnosed late in life and often do not achieve adequate LDL-C lowering, despite a high prevalence of coronary heart disease and risk factors. These findings highlight the need for earlier diagnosis of FH and initiation of lipid-lowering therapy, more consistent use of guideline-recommended LDL-lowering therapy, and comprehensive management of traditional coronary heart disease risk factors.

Cholesteryl Ester Transfer Protein Inhibition With Anacetrapib Decreases Fractional Clearance Rates of High-Density Lipoprotein Apolipoprotein A-I and Plasma Cholesteryl Ester Transfer Protein.

OBJECTIVE: Anacetrapib (ANA), an inhibitor of cholesteryl ester transfer protein (CETP) activity, increases plasma concentrations of high-density lipoprotein cholesterol (HDL-C), apolipoprotein A-I (apoA)-I, apoA-II, and CETP. The mechanisms responsible for these treatment-related increases in apolipoproteins and plasma CETP are unknown. We performed a randomized, placebo (PBO)-controlled, double-blind, fixed-sequence study to examine the effects of ANA on the metabolism of HDL apoA-I and apoA-II and plasma CETP. APPROACH AND RESULTS: Twenty-nine participants received atorvastatin (ATV) 20 mg/d plus PBO for 4 weeks, followed by ATV plus ANA 100 mg/d for 8 weeks (ATV-ANA). Ten participants received double PBO for 4 weeks followed by PBO plus ANA for 8 weeks (PBO-ANA). At the end of each treatment, we examined the kinetics of HDL apoA-I, HDL apoA-II, and plasma CETP after D3-leucine administration as well as 2D gel analysis of HDL subspecies. In the combined ATV-ANA and PBO-ANA groups, ANA treatment increased plasma HDL-C (63.0%; P<0.001) and apoA-I levels (29.5%; P<0.001). These increases were associated with reductions in HDL apoA-I fractional clearance rate (18.2%; P=0.002) without changes in production rate. Although the apoA-II levels increased by 12.6% (P<0.001), we could not discern significant changes in either apoA-II fractional clearance rate or production rate. CETP levels increased 102% (P<0.001) on ANA because of a significant reduction in the fractional clearance rate of CETP (57.6%, P<0.001) with no change in CETP production rate. CONCLUSIONS: ANA treatment increases HDL apoA-I and CETP levels by decreasing the fractional clearance rate of each protein.

Updated cholesterol guidelines and intensity of statin therapy.

BACKGROUND: In November 2013, the American College of Cardiology and the American Heart Association released new cholesterol guidelines. Implications of these new guidelines for statin prescription remain uncertain, particularly in individuals already on statin therapy. OBJECTIVE: Our objective was to examine the impact of the guidelines on the intensity of statin therapy at a large academic medical center. METHODS: We queried the electronic health record at the University of Pennsylvania Health System to evaluate current practice patterns at a large academic institution in patients already on statin therapy. RESULTS: Among 40,036 statin-treated patients, 47% of patients may warrant an intensification of statin therapy according to the updated national cholesterol guidelines. CONCLUSIONS: These findings highlight the magnitude of potential changes in statin prescription patterns favoring higher potency statin therapy, a sizable shift that parallels the predicted increase in statin initiation.

Anacetrapib lowers LDL by increasing ApoB clearance in mildly hypercholesterolemic subjects.

BACKGROUND: Individuals treated with the cholesteryl ester transfer protein (CETP) inhibitor anacetrapib exhibit a reduction in both LDL cholesterol and apolipoprotein B (ApoB) in response to monotherapy or combination therapy with a statin. It is not clear how anacetrapib exerts these effects; therefore, the goal of this study was to determine the kinetic mechanism responsible for the reduction in LDL and ApoB in response to anacetrapib. METHODS: We performed a trial of the effects of anacetrapib on ApoB kinetics. Mildly hypercholesterolemic subjects were randomized to background treatment of either placebo (n = 10) or 20 mg atorvastatin (ATV) (n = 29) for 4 weeks. All subjects then added 100 mg anacetrapib to background treatment for 8 weeks. Following each study period, subjects underwent a metabolic study to determine the LDL-ApoB-100 and proprotein convertase subtilisin/kexin type 9 (PCSK9) production rate (PR) and fractional catabolic rate (FCR). RESULTS: Anacetrapib markedly reduced the LDL-ApoB-100 pool size (PS) in both the placebo and ATV groups. These changes in PS resulted from substantial increases in LDL-ApoB-100 FCRs in both groups. Anacetrapib had no effect on LDL-ApoB-100 PRs in either treatment group. Moreover, there were no changes in the PCSK9 PS, FCR, or PR in either group. Anacetrapib treatment was associated with considerable increases in the LDL triglyceride/cholesterol ratio and LDL size by NMR. CONCLUSION: These data indicate that anacetrapib, given alone or in combination with a statin, reduces LDL-ApoB-100 levels by increasing the rate of ApoB-100 fractional clearance. TRIAL REGISTRATION: ClinicalTrials.gov NCT00990808. FUNDING: Merck & Co. Inc., Kenilworth, New Jersey, USA. Additional support for instrumentation was obtained from the National Center for Advancing Translational Sciences (UL1TR000003 and UL1TR000040).

A pilot trial to examine the effect of high-dose niacin on arterial wall inflammation using fluorodeoxyglucose positron emission tomography.

RATIONALE AND OBJECTIVES: Although studies have reported direct inhibition of inflammatory pathways with niacin, the effect of niacin on arterial wall inflammation remains unknown. We examined the effect of niacin on arterial (18)F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT). MATERIALS AND METHODS: Nine statin-treated patients with coronary disease were randomized to niacin 6000 mg/day or placebo. FDG-PET/CT and lipids were assessed at baseline and at 12 weeks. FDG was quantified in the aorta, right carotid artery, and left carotid artery as the target-to-background ratio (TBR) and target-to-background difference (TBD). RESULTS: Eight patients completed the study. No significant changes in FDG measured by aortic, left carotid, or right carotid TBR or TBD were seen in either group. Compared to baseline, niacin-treated subjects exhibited a significant 29% reduction in low-density lipoprotein cholesterol (LDL-C; 95% confidence interval [CI], -50% to 8%; P = .01) and a nonsignificant 29% reduction in LDL particle number (LDL-P; 95% CI, -58% to 0.2%; P = .07). A nonsignificant 11% increase in HDL-C (95% CI, -15% to 37%; P = .30) and 8% decrease in HDL-P (95% CI, -44% to 28%; P = .51) were observed with niacin treatment. In a pooled analysis, changes in LDL-P were positively correlated with FDG uptake in the aorta (TBR r = 0.66, P = .08; TBD r = 0.75, P = .03), left carotid (TBR r = 0.65, P = .08; TBD r = 0.74, P = .03), and right carotid (TBR r = 0.54, P = .17; TBD r = 0.61, P = .11). CONCLUSIONS: In this pilot study, adding niacin to statin therapy did not affect arterial wall inflammation measured by FDG-PET/CT. However, an association between changes in arterial FDG uptake and LDL-P was observed. Larger studies are needed to definitively examine the effect of niacin on arterial wall inflammation.

Statins and cognitive function: an updated review.

Ischemic heart disease remains the leading cause of death in the USA. Statins have substantially contributed to the decline in mortality due to heart disease. Historically, statins are hypothesized to be neuroprotective and beneficial in dementia, but recent reports have suggested an association with transient cognitive decline. We have critically appraised the relationship between statins and cognitive function in this review. Most of the data are observational and reported a protective effect of statins on dementia and Alzheimer's disease in patients with normal cognition at baseline. Few studies, including two randomized control trials, were unable to find a statistically significant decrease in the risk or improvement in patients with established dementia or decline in cognitive function with statin use. As more randomized control trials are required to definitively settle this, cardiovascular benefits of statins must be weighed against the risks of cognitive decline on an individual basis.

Lomitapide for the management of homozygous familial hypercholesterolemia.

Homozygous familial hypercholesterolemia (HoFH) is a rare genetic disorder of low-density lipoprotein cholesterol (LDL-C) metabolism resulting in extremely elevated serum levels of LDL-C and premature atherosclerotic cardiovascular disease. Treatment typically involves multiple pharmacologic agents, as well as mechanical filtration using weekly or biweekly LDL apheresis. Despite combination lipid-lowering therapy, LDL-C levels and cardiovascular morbidity and mortality remain unacceptably high in HoFH patients. The European Commission and the US Food and Drug Administration approved the use of lomitapide, a novel medication designed to address this significant unmet need. Lomitapide is an orally administered inhibitor of microsomal triglyceride transfer protein that is indicated as an adjunct to a low-fat diet and other lipid-lowering treatments, including LDL apheresis where available for the reduction of LDL-C, total cholesterol, apolipoprotein B, and non-high-density lipoprotein cholesterol in adult patients with HoFH. The risks of transaminase elevations, hepatic steatosis, and gastrointestinal side effects, and the potential for drug interactions, require vigilant examination of the clinical and laboratory data and patient counseling prior to initiation of lomitapide, as well as regular monitoring during follow-up care. This article highlights important practical considerations for the use of lomitapide in the context of the evaluation and management of a HoFH patient case.

Future of cholesteryl ester transfer protein inhibitors.

The cholesteryl ester transfer protein (CETP) plays an integral role in the metabolism of plasma lipoproteins. Despite two failures, CETP inhibitors are still in clinical development. We review the genetics of CETP and coronary disease, preclinical data on CETP inhibition and atherosclerosis, and the effects of CETP inhibition on cholesterol efflux and reverse cholesterol transport. We discuss the two failed CETP inhibitors, torcetrapib and dalcetrapib, and attempt to extract lessons learned. Two CETP inhibitors, anacetrapib and evacetrapib, are in phase III development, and we attempt to differentiate them from the failed drugs. Whether pharmacologic CETP inhibition will reduce the risk of cardiovascular disease is one of the most fascinating and important questions in the field of cardiovascular medicine.

Statins and cognitive function: a systematic review.

BACKGROUND: Despite the U.S. Food and Drug Administration (FDA) warning regarding cognitive impairment, the relationship between statins and cognition remains unknown. PURPOSE: To examine the effect of statins on cognition. DATA SOURCES: PubMed, Embase, and Cochrane Library from inception through October 2012; FDA databases from January 1986 through March 2012. STUDY SELECTION: Randomized, controlled trials (RCTs) and cohort, case-control, and cross-sectional studies evaluating cognition in patients receiving statins. DATA EXTRACTION: Two reviewers extracted data, 1 reviewer assessed study risk of bias, and 1 reviewer checked all assessments. DATA SYNTHESIS: Among statin users, low-quality evidence suggested no increased incidence of Alzheimer disease and no difference in cognitive performance related to procedural memory, attention, or motor speed. Moderate-quality evidence suggested no increased incidence of dementia or mild cognitive impairment or any change in cognitive performance related to global cognitive performance scores, executive function, declarative memory, processing speed, or visuoperception. Examination of the FDA postmarketing surveillance databases revealed a low reporting rate for cognitive-related adverse events with statins that was similar to the rates seen with other commonly prescribed cardiovascular medications. LIMITATIONS: The absence of many well-powered RCTs for most outcomes resulted in final strengths of evidence that were low or moderate. Imprecision, inconsistency, and risk of bias also limited the strength of findings. CONCLUSION: Larger and better-designed studies are needed to draw unequivocal conclusions about the effect of statins on cognition. Published data do not suggest an adverse effect of statins on cognition; however, the strength of available evidence is limited, particularly with regard to high-dose statins.

Discordance between non-HDL-cholesterol and LDL-particle measurements: results from the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Cardiovascular risk assessment incorporates measurement of atherogenic lipids such as non-HDL cholesterol (non-HDL-C). It remains uncertain under which circumstances atherogenic lipoprotein enumeration such as LDL particle number (LDL-P) differs from simultaneously acquired non-HDL-C. METHODS: Participants of the Multi-Ethnic Study of Atherosclerosis (MESA) were deemed LDL-P > non-HDL-C discordant if they exhibited higher LDL-P than expected for simultaneously measured non-HDL-C, given the observed distribution of both in MESA. Conversely, a lower LDL-P than would be suggested from non-HDL-C characterized LDL-P < non-HDL-C discordance. Regression models were used to estimate associations of demographics and comorbidities with discordance and of LDL-P and non-HDL-C with carotid intima-media thickness (CIMT) and detectable coronary artery calcium (CAC) among discordance groups. RESULTS: Discordance was observed among 44% of subjects. LDL-P > non-HDL-C compared to LDL-P < non-HDL-C discordance was more common among Hispanics and smokers; among subjects with lower HDL-C, lower triglycerides, or greater insulin resistance by homeostatic model assessment of insulin resistance (HOMA-IR); and among subjects on lipid-lowering therapy, anti-hypertensive therapy, or hormone replacement therapy. In the setting of discordance, LDL-P exhibited a modestly greater association with CIMT than did non-HDL-C (+0.024-0.025 mm vs +0.018-0.021 mm per SD increase). In the presence of LDL-P < non-HDL-C discordance, LDL-P demonstrated a modestly greater association with detectable CAC than did non-HDL-C (OR 1.51 vs 1.46 per SD increase). CONCLUSIONS: Our results demonstrated that disagreement between LDL-P and non-HDL-C was common and significantly associated with several clinical characteristics. In the setting of discordance, LDL-P was more closely associated with CIMT and CAC than non-HDL-C, though observed differences were small.

Pharmacologic interactions of multidrug therapy for dyslipidemia.

Despite the best available medical therapy inclusive of statins, substantial residual risk remains for atherothrombotic cardiovascular disease. Non-statin lipid-lowering therapy may help address this critical unmet need through reduction of the levels of low-density lipoprotein and other atherogenic lipoproteins. In the past few years, several landmark trials have provided important information regarding the efficacy and safety of non-statin therapy for dyslipidemia and cardiovascular risk reduction.

Differences in absolute risk of cardiovascular events using risk-refinement tests: a systematic analysis of four cardiovascular risk equations.

BACKGROUND: Current cardiovascular risk assessment guidelines incorporate judicious use of C-reactive protein (CRP), carotid intima-media thickness (CIMT), and coronary artery calcium (CAC) in selected populations and describe threshold levels for higher and lower cardiovascular risk for each of the three risk refinement tests. However, the effect of these suggested thresholds of relative risk on absolute global risk remains uncertain. METHODS: Systematic permutation of risk factors provided 10-year risk estimates using the Framingham risk score, equations derived from the Multi-Ethnic Study of Atherosclerosis (MESA) and the Atherosclerosis Risk in Communities (ARIC) study, and the Reynolds risk score. Low-, high-, and very-high-risk values of CAC, CIMT, and hsCRP were defined as: 0, 100, 400 Agatston units; 25th percentile without plaque, 75th percentile without plaque, 75th percentile with plaque; and 1.0, 3.0, 7.0 mg/L. RESULTS: Incorporation of low-, high-, and very-high-risk CAC values using the MESA risk score resulted in greater changes in absolute risk from the Framingham risk score than the addition of either CIMT or hsCRP values using the ARIC or Reynolds risk scores. CONCLUSIONS: Although certain values of CAC, CIMT, and hsCRP have been similarly designated as low, high, or very-high risk, incorporation of these thresholds into validated risk equations yielded substantially different levels of absolute cardiovascular risk. Use of available risk equations may be advisable to calculate absolute risk rather than relying on risk-marker thresholds derived from relative risk estimates.