Todd C. Villines

Extended-Release Niacin or Ezetimibe and Carotid Intima–Media Thickness

BACKGROUND Treatment added to statin monotherapy to further modify the lipid profile may include combination therapy to either raise the high-density lipoprotein (HDL) cholesterol level or further lower the low-density lipoprotein (LDL) cholesterol level. METHODS We enrolled patients who had coronary heart disease or a coronary heart disease risk equivalent, who were receiving long-term statin therapy, and in whom an LDL cholesterol level under 100 mg per deciliter (2.6 mmol per liter) and an HDL cholesterol level under 50 mg per deciliter for men or 55 mg per deciliter for women (1.3 or 1.4 mmol per liter, respectively) had been achieved. The patients were randomly assigned to receive extended-release niacin (target dose, 2000 mg per day) or ezetimibe (10 mg per day). The primary end point was the between-group difference in the change from baseline in the mean common carotid intima-media thickness after 14 months. The trial was terminated early, on the basis of efficacy, according to a prespecified analysis conducted after 208 patients had completed the trial. RESULTS The mean HDL cholesterol level in the niacin group increased by 18.4% over the 14-month study period, to 50 mg per deciliter (P < 0.001), and the mean LDL cholesterol level in the ezetimibe group decreased by 19.2%, to 66 mg per deciliter (1.7 mmol per liter) (P < 0.001). Niacin therapy significantly reduced LDL cholesterol and triglyceride levels; ezetimibe reduced the HDL cholesterol and triglyceride levels. As compared with ezetimibe, niacin had greater efficacy regarding the change in mean carotid intima-media thickness over 14 months (P = 0.003), leading to significant reduction of both mean (P = 0.001) and maximal carotid intima-media thickness (P < or = 0.001 for all comparisons). Paradoxically, greater reductions in the LDL cholesterol level in association with ezetimibe were significantly associated with an increase in the carotid intima-media thickness (R = -0.31, P < 0.001). The incidence of major cardiovascular events was lower in the niacin group than in the ezetimibe group (1% vs. 5%, P = 0.04 by the chi-square test). CONCLUSIONS This comparative-effectiveness trial shows that the use of extended-release niacin causes a significant regression of carotid intima-media thickness when combined with a statin and that niacin is superior to ezetimibe. (ClinicalTrials.gov number, NCT00397657.)

Age- and Sex-Related Differences in All-Cause Mortality Risk Based on Coronary Computed Tomography Angiography Findings Results From the International Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry) of 23,854 Patients Without Known Coronary Artery Disease

OBJECTIVES We examined mortality in relation to coronary artery disease (CAD) as assessed by ≥64-detector row coronary computed tomography angiography (CCTA). BACKGROUND Although CCTA has demonstrated high diagnostic performance for detection and exclusion of obstructive CAD, the prognostic findings of CAD by CCTA have not, to date, been examined for age- and sex-specific outcomes. METHODS We evaluated a consecutive cohort of 24,775 patients undergoing ≥64-detector row CCTA between 2005 and 2009 without known CAD who met inclusion criteria. In these patients, CAD by CCTA was defined as none (0% stenosis), mild (1% to 49% stenosis), moderate (50% to 69% stenosis), or severe (≥70% stenosis). CAD severity was judged on a per-patient, per-vessel, and per-segment basis. Time to mortality was estimated using multivariable Cox proportional hazards models. RESULTS At a 2.3 ± 1.1-year follow-up, 404 deaths had occurred. In risk-adjusted analysis, both per-patient obstructive (hazard ratio [HR]: 2.60; 95% confidence interval [CI]: 1.94 to 3.49; p < 0.0001) and nonobstructive (HR: 1.60; 95% CI: 1.18 to 2.16; p = 0.002) CAD conferred increased risk of mortality compared with patients without evident CAD. Incident mortality was associated with a dose-response relationship to the number of coronary vessels exhibiting obstructive CAD, with increasing risk observed for nonobstructive (HR: 1.62; 95% CI: 1.20 to 2.19; p = 0.002), obstructive 1-vessel (HR: 2.00; 95% CI: 1.43 to 2.82; p < 0.0001), 2-vessel (HR: 2.92; 95% CI: 2.00 to 4.25; p < 0.0001), or 3-vessel or left main (HR: 3.70; 95% CI: 2.58 to 5.29; p < 0.0001) CAD. Importantly, the absence of CAD by CCTA was associated with a low rate of incident death (annualized death rate: 0.28%). When stratified by age <65 years versus ≥65 years, younger patients experienced higher hazards for death for 2-vessel (HR: 4.00; 95% CI: 2.16 to 7.40; p < 0.0001 vs. HR: 2.46; 95% CI: 1.51 to 4.02; p = 0.0003) and 3-vessel (HR: 6.19; 95% CI: 3.43 to 11.2; p < 0.0001 vs. HR: 3.10; 95% CI: 1.95 to 4.92; p < 0.0001) CAD. The relative hazard for 3-vessel CAD (HR: 4.21; 95% CI: 2.47 to 7.18; p < 0.0001 vs. HR: 3.27; 95% CI: 1.96 to 5.45; p < 0.0001) was higher for women as compared with men. CONCLUSIONS Among individuals without known CAD, nonobstructive and obstructive CAD by CCTA are associated with higher rates of mortality, with risk profiles differing for age and sex. Importantly, absence of CAD is associated with a very favorable prognosis.

Prognostic value of cardiac computed tomography angiography: a systematic review and meta-analysis.

OBJECTIVES The purpose of this study was to systematically review and perform a meta-analysis of the ability of cardiac computed tomography angiography (CCTA) to predict future cardiovascular events and death. BACKGROUND The diagnostic accuracy of CCTA is well reported. The prognostic value of CCTA has been described in several studies, but many were underpowered. Pooling outcomes increases the power to predict rare events. METHODS We searched multiple databases for longitudinal studies of CCTA with at least 3 months follow-up of symptomatic patients with suspected coronary artery disease (CAD) reporting major adverse cardiovascular events (MACE), consisting of death, myocardial infarction (MI), and revascularization. Annualized event rates were pooled using a bivariate mixed-effects binomial regression model to calculate summary likelihood ratios and receiver-operating characteristic curves. RESULTS Eighteen studies evaluated 9,592 patients with a median follow-up of 20 months. The pooled annualized event rate for obstructive (any vessel with >50% luminal stenosis) versus normal CCTA was 8.8% versus 0.17% per year for MACE (p < 0.05) and 3.2% versus 0.15% for death or MI (p < 0.05). The pooled negative likelihood ratio for MACE after normal CCTA findings was 0.008 (95% confidence interval [CI]: 0.0004 to 0.17, p < 0.001), the positive likelihood ratio was 1.70 (95% CI: 1.42 to 2.02, p < 0.001), sensitivity was 0.99 (95% CI: 0.93 to 1.00, p < 0.001), and specificity was 0.41 (95% CI: 0.31 to 0.52, p < 0.001). Stratifying by no CAD, nonobstructive CAD (worst stenosis <50%), or obstructive CAD, there were incrementally increasing adverse events. CONCLUSIONS Adverse cardiovascular events among patients with normal findings on CCTA are rare. There are incrementally increasing future MACE with increasing CAD by CCTA.

The ARBITER 6-HALTS Trial (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies in Atherosclerosis): Final Results and the Impact of Medication Adherence, Dose, and Treatment Duration

OBJECTIVES This report describes the final results of the ARBITER 6-HALTS (Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis) trial. BACKGROUND The ARBITER 6-HALTS trial was terminated early on the basis of a pre-specified interim analysis showing superiority of niacin over ezetimibe on change in carotid intima-media thickness (CIMT). After termination, an additional 107 subjects completed a close-out assessment. METHODS Patients with coronary heart disease (CHD) or CHD equivalent with low-density lipoprotein cholesterol <100 mg/dl and high-density lipoprotein cholesterol <50 mg/dl for men or 55 mg/dl for women while receiving stable statin treatment were randomly assigned to ezetimibe (10 mg/day) or extended-release niacin (target dose, 2,000 mg/day). The primary end point was change in mean CIMT, analyzed according to a last observation carried forward method. The relationships of study medication adherence, dosage, and cumulative exposure (product of adherence, dose, and time) with change in CIMT were explored. RESULTS Results in 315 patients included 208 with 14-month follow-up and 107 after mean treatment of 7 +/- 3 months. Niacin (n = 154) resulted in significant reduction (regression) in mean CIMT (-0.0102 +/- 0.0026 mm; p < 0.001) and maximal CIMT (-0.0124 +/- 0.0036 mm; p = 0.001), whereas ezetimibe (n = 161) did not reduce mean CIMT (-0.0016 +/- 0.0024 mm; p = 0.88) or maximal CIMT (-0.0005 +/- 0.0029 mm; p = 0.88) compared with baseline. There was a significant difference between ezetimibe and niacin treatment groups on mean changes in CIMT, favoring niacin, for both mean CIMT (p = 0.016) and maximal CIMT (p = 0.01). Increased cumulative drug exposure was related to regression of CIMT with niacin, and progression of CIMT with ezetimibe. CONCLUSIONS Niacin induces regression of CIMT and is superior to ezetimibe for patients taking statins. (Comparative Study of the Effect of Ezetimibe Versus Extended-Release Niacin on Atherosclerosis; NCT00397657).

Prevalence and Severity of Coronary Artery Disease and Adverse Events Among Symptomatic Patients With Coronary Artery Calcification Scores of Zero Undergoing Coronary Computed Tomography Angiography Results From the CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) Registry

OBJECTIVES The purpose of this study was to describe the prevalence and severity of coronary artery disease (CAD) in relation to prognosis in symptomatic patients without coronary artery calcification (CAC) undergoing coronary computed tomography angiography (CCTA). BACKGROUND The frequency and clinical relevance of CAD in patients without CAC are unclear. METHODS We identified 10,037 symptomatic patients without CAD who underwent concomitant CCTA and CAC scoring. CAD was assessed as <50%, ≥50%, and ≥70% stenosis. All-cause mortality and the composite endpoint of mortality, myocardial infarction, or late coronary revascularization (≥90 days after CCTA) were assessed. RESULTS Mean age was 57 years, 56% were men, and 51% had a CAC score of 0. Among patients with a CAC score of 0, 84% had no CAD, 13% had nonobstructive stenosis, and 3.5% had ≥50% stenosis (1.4% had ≥70% stenosis) on CCTA. A CAC score >0 had a sensitivity, specificity, and negative and positive predictive values for stenosis ≥50% of 89%, 59%, 96%, and 29%, respectively. During a median of 2.1 years, there was no difference in mortality among patients with a CAC score of 0 irrespective of obstructive CAD. Among 8,907 patients with follow-up for the composite endpoint, 3.9% with a CAC score of 0 and ≥50% stenosis experienced an event (hazard ratio: 5.7; 95% confidence interval: 2.5 to 13.1; p < 0.001) compared with 0.8% of patients with a CAC score of 0 and no obstructive CAD. Receiver-operator characteristic curve analysis demonstrated that the CAC score did not add incremental prognostic information compared with CAD extent on CCTA for the composite endpoint (CCTA area under the curve = 0.825; CAC + CCTA area under the curve = 0.826; p = 0.84). CONCLUSIONS In symptomatic patients with a CAC score of 0, obstructive CAD is possible and is associated with increased cardiovascular events. CAC scoring did not add incremental prognostic information to CCTA.

Coronary Computed Tomographic Angiography and Risk of All-Cause Mortality and Nonfatal Myocardial Infarction in Subjects Without Chest Pain Syndrome From the CONFIRM Registry (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter Registry)

Background— The predictive value of coronary computed tomographic angiography (cCTA) in subjects without chest pain syndrome (CPS) has not been established. We investigated the prognostic value of coronary artery disease detection by cCTA and determined the incremental risk stratification benefit of cCTA findings compared with clinical risk factor scoring and coronary artery calcium scoring (CACS) for individuals without CPS. Methods and Results— An open-label, 12-center, 6-country observational registry of 27 125 consecutive patients undergoing cCTA and CACS was queried, and 7590 individuals without CPS or history of coronary artery disease met the inclusion criteria. All-cause mortality and the composite of all-cause mortality and nonfatal myocardial infarction were measured. During a median follow-up of 24 months (interquartile range, 18–35 months), all-cause mortality occurred in 136 individuals. After risk adjustment, compared with individuals without evidence of coronary artery disease by cCTA, individuals with obstructive 2- and 3-vessel disease or left main coronary artery disease experienced higher rates of death and composite outcome (P<0.05 for both). Both CACS and cCTA significantly improved the performance of standard risk factor prediction models for all-cause mortality and the composite outcome (likelihood ratio P<0.05 for all), but the incremental discriminatory value associated with their inclusion was more pronounced for the composite outcome and for CACS (C statistic for model with risk factors only was 0.71; for risk factors plus CACS, 0.75; for risk factors plus CACS plus cCTA, 0.77). The net reclassification improvement resulting from the addition of cCTA to a model based on standard risk factors and CACS was negligible. Conclusions— Although the prognosis for individuals without CPS is stratified by cCTA, the additional risk-predictive advantage by cCTA is not clinically meaningful compared with a risk model based on CACS. Therefore, at present, the application of cCTA for risk assessment of individuals without CPS should not be justified.

Outcomes After Coronary Computed Tomography Angiography in the Emergency Department: A Systematic Review and Meta-Analysis of Randomized, Controlled Trials

OBJECTIVES The aim of the study was to systematically review and perform a meta-analysis of randomized, controlled trials of coronary computed tomography angiography (CCTA) versus usual care (UC) triage of acute chest pain in the emergency department (ED). BACKGROUND CCTA allows rapid evaluation of patients presenting to the ED with acute chest pain syndromes; however, the impact of such testing on patient management and downstream testing has emerged as a concern. METHODS We systematically searched for randomized, controlled trials of CCTA in the ED and performed a meta-analysis of clinical outcomes. RESULTS Four randomized, controlled trials were included, with 1,869 patients undergoing CCTA and 1,397 undergoing UC. There were no deaths and no difference in the incidence of myocardial infarction, post-discharge ED visits, or rehospitalizations. Four studies reported decreased length of stay with CCTA and 3 reported cost savings; 8.4% of patients undergoing CCTA versus 6.3% of those receiving UC underwent invasive coronary angiography (ICA), whereas 4.6% of patients undergoing CCTA versus 2.6% of those receiving UC underwent coronary revascularization. The odds ratio of ICA for CCTA patients versus UC patients was 1.36 (95% confidence interval [CI]: 1.03 to 1.80, p = 0.030), and for revascularization, it was 1.81 (95% CI: 1.20 to 2.72, p = 0.004). The absolute increase in ICA after CCTA was 21 per 1,000 CCTA patients (95% CI: 1.8 to 44.9), and the number needed to scan was 48. The absolute increase in revascularization after CCTA was 20 per 1,000 patients (95% CI: 5.0 to 41.4); the number needed to scan was 50. Both percutaneous coronary intervention and coronary artery bypass graft surgery independently contributed to the significant increase in revascularization. CONCLUSIONS Compared with UC, the use of CCTA in the ED is associated with decreased ED cost and length of stay but increased ICA and revascularization.

Coronary Computed Tomographic Angiography as a Gatekeeper to Invasive Diagnostic and Surgical Procedures : Results From the Multicenter CONFIRM (Coronary CT Angiography Evaluation for Clinical Outcomes: An International Multicenter) Registry

OBJECTIVES This study sought to examine patterns of follow-up invasive coronary angiography (ICA) and revascularization (REV) after coronary computed tomography angiography (CCTA). BACKGROUND CCTA is a noninvasive test that permits direct visualization of the extent and severity of coronary artery disease (CAD). Post-CCTA patterns of follow-up ICA and REV are incompletely defined. METHODS We examined 15,207 intermediate likelihood patients from 8 sites in 6 countries; these patients were without known CAD, underwent CCTA, and were followed up for 2.3 ± 1.2 years for all-cause mortality. Coronary artery stenosis was judged as obstructive when ≥50% stenosis was present. A multivariable logistic regression was used to estimate ICA use. A Cox proportional hazards model was used to estimate all-cause mortality. RESULTS During follow-up, ICA rates for patients with no CAD to mild CAD according to CCTA were low (2.5% and 8.3%), with similarly low rates of REV (0.3% and 2.5%). Most ICA procedures (79%) occurred ≤3 months of CCTA. Obstructive CAD was associated with higher rates of ICA and REV for 1-vessel (44.3% and 28.0%), 2-vessel (53.3% and 43.6%), and 3-vessel (69.4% and 66.8%) CAD, respectively. For patients with <50% stenosis, early ICA rates were elevated; over the entirety of follow-up, predictors of ICA were mild left main, mild proximal CAD, respectively, or higher coronary calcium scores. In patients with <50% stenosis, the relative hazard for death was 2.2 (p = 0.011) for ICA versus no ICA. Conversely, for patients with CAD, the relative hazard for death was 0.61 for ICA versus no ICA (p = 0.047). CONCLUSIONS These findings support the concept that CCTA may be used effectively as a gatekeeper to ICA.

Optimized Prognostic Score for Coronary Computed Tomographic Angiography: Results From the CONFIRM Registry (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter Registry)

OBJECTIVES The aim of this study was to analyze the predictive value of coronary computed tomography angiography (CCTA) and to model and validate an optimized score for prognosis of 2-year survival on the basis of a patient population with suspected coronary artery disease (CAD). BACKGROUND Coronary computed tomography angiography carries important prognostic information in addition to the detection of obstructive CAD. But it is still unclear how the results of CCTA should be interpreted in the context of clinical risk predictors. METHODS The analysis is based on a test sample of 17,793 patients and a validation sample of 2,506 patients, all with suspected CAD, from the international CONFIRM (COronary CT Angiography EvaluatioN For Clinical Outcomes: An InteRnational Multicenter) registry. On the basis of CCTA data and clinical risk scores, an optimized score was modeled. The endpoint was all-cause mortality. RESULTS During a median follow-up of 2.3 years, 347 patients died. The best CCTA parameter for prediction of mortality was the number of proximal segments with mixed or calcified plaques (C-index 0.64, p < 0.0001) and the number of proximal segments with a stenosis >50% (C-index 0.56, p = 0.002). In an optimized score including both parameters, CCTA significantly improved overall risk prediction beyond National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) score as best clinical score. According to this score, a proximal segment with either a mixed or calcified plaque or a stenosis >50% is equivalent to a 5-year increase in age or the risk of smoking. CONCLUSIONS In CCTA, both plaque burden and stenosis, particularly in proximal segments, carry incremental prognostic value. A prognostic score on the basis of this data can improve risk prediction beyond clinical risk scores.

HIV positivity, protease inhibitor exposure, and subclinical atherosclerosis: A systematic review and meta-analysis of observational studies

Context: Patients with HIV may have increased risk of atherosclerotic cardiovascular disease owing to multiple biological mechanisms. Objective: To evaluate the evidence for subclinical atherosclerosis among patients with HIV. Design: Systematic review of observational studies. Data sources: We searched Medline, Cochrane DSR, ACP Journal Club, DARE, CMR, HTA, NHSEED, Embase and the Cochrane Controlled Trials Register for studies published before November 2008. Study selection: Eligible studies were cross-sectional, cohort, or case–control studies reporting carotid ultrasound intima-media thickness (CIMT), focal plaque incidence, or coronary artery calcium (CAC), as determined by HIV positivity or protease inhibitor (PI) exposure. Data extraction: Two independent reviewers abstracted data using a standardised form. The primary outcome was weighted mean difference (WMD) for CIMT comparing HIV positive versus negative patients. Other outcomes included WMD by PI exposure and the odds ratio (OR) for a focal carotid plaque or CAC. Data from six cross-sectional, seven case–control and 13 cohort studies were included, involving 5456 HIV positive and 3600 HIV negative patients. Results: The weighted mean CIMT was 0.04 mm thicker among patients with HIV than among non-HIV patients (95% CI 0.02 to 0.06; p<0.001). HIV positivity was not associated with carotid plaque or CAC. PI exposure did not significantly affect CIMT, carotid plaque, or CAC. There was evidence of publication bias and stratified analysis and meta-regression showed outcomes were influenced by study design, age, gender and smoking. However, HIV positivity slightly increased CIMT even after sensitivity analyses. Conclusions: HIV infection and PI exposure are not strong independent risk factors for subclinical atherosclerosis. Confounding may contribute to overestimation of the risk associated with HIV and PI exposure.