Evinacumab in homozygous familial hypercholesterolaemia: long-term safety and efficacy.

BACKGROUND AND AIMS: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disorder characterized by severely elevated LDL cholesterol (LDL-C) and premature atherosclerotic cardiovascular disease. In the pivotal Phase 3 HoFH trial (NCT03399786), evinacumab significantly decreased LDL-C in patients with HoFH. This study assesses the long-term safety and efficacy of evinacumab in adult and adolescent patients with HoFH. METHODS: In this open-label, single-arm, Phase 3 trial (NCT03409744), patients aged ≥12 years with HoFH who were evinacumab-naïve or had previously received evinacumab in other trials (evinacumab-continue) received intravenous evinacumab 15 mg/kg every 4 weeks with stable lipid-lowering therapy. RESULTS: A total of 116 patients (adults: n = 102; adolescents: n = 14) were enrolled, of whom 57 (49.1%) were female. Patients were treated for a median (range) duration of 104.3 (28.3-196.3) weeks. Overall, treatment-emergent adverse events (TEAEs) and serious TEAEs were reported in 93 (80.2%) and 27 (23.3%) patients, respectively. Two (1.7%) deaths were reported (neither was considered related to evinacumab). Three (2.6%) patients discontinued due to TEAEs (none were considered related to evinacumab). From baseline to Week 24, evinacumab decreased mean LDL-C by 43.6% [mean (standard deviation, SD), 3.4 (3.2) mmol/L] in the overall population; mean LDL-C reduction in adults and adolescents was 41.7% [mean (SD), 3.2 (3.3) mmol/L] and 55.4% [mean (SD), 4.7 (2.5) mmol/L], respectively. CONCLUSIONS: In this large cohort of patients with HoFH, evinacumab was generally well tolerated and markedly decreased LDL-C irrespective of age and sex. Moreover, the efficacy and safety of evinacumab was sustained over the long term.

Poor cardiovascular health status among Chinese women.

BACKGROUND: Systematic investigation and analysis of cardiovascular health status (CVHS) of Chinese women is rare. This study aimed to assess CVHS and atherosclerotic cardiovascular disease (ASCVD) burden in the Chinese women physicians (CWP) and community-based non-physician cohort (NPC). METHODS: In this prospective, multicenter, observational study, CVHS using the American Heart Association (AHA) defined 7 metrics (such as smoking and fasting glucose) and ASCVD risk factors including hypertension, hyperlipidemia and type-2 diabetes were evaluated in CWP compared with NPC. RESULTS: Of 5832 CWP with a mean age of 44 ± 7 years, only 1.2% achieved the ideal CVHS and 90.1% showed at least 1 of the 7 AHA CVHS metrics at a poor level. Total CVHS score was significantly decreased and ASCVD risk burden was increased in postmenopausal subjects in CWP although ideal CVHS was not significantly influenced by menopause. Compared to 2596 NPC, fewer CWP had ≥ 2 risk factors (8% vs. 27%, P < 0.001); CWP scored significantly higher on healthy factors, a composite of total cholesterol, blood pressure, fasting glucose (P < 0.001), but, poorly on healthy behaviors (P < 0.001), specifically in the physical activity component; CWP also showed significantly higher levels of awareness and rates of treatment for hypertension and hyperlipidemia, but, not for type-2 diabetes. CONCLUSION: Chinese women's cardiovascular health is far from ideal and risk intervention is sub-optimal. Women physicians had lower ASCVD burden, scored higher in healthy factors, but, took part in less physical activity than the non-physician cohort. These results call for population-specific early and improved risk intervention.

High-resolution MRI assessed carotid atherosclerotic plaque characteristics comparing men and women with elevated ApoB levels.

Previous studies demonstrated that men were more likely to have plaque rupture and are at greater risk for myocardial infarction and stroke than women. We evaluated differences in carotid plaque characteristics by MRI between men and women with mild-moderate atherosclerosis and elevated ApoB levels. One hundred eighty-two subjects (104 men and 78 women) with CAD or carotid stenosis (≥ 15% by ultrasound), ApoB ≥ 120 mg/dL and carotid MRI scan were included. Percent wall volume (%WV) was calculated as (wall volume/total vessel volume) × 100%. Three major plaque compositions, fibrous tissue (FT), calcification (CA) and lipid rich necrotic core (LRNC), were identified and quantified using published MRI criteria. Adventitial and plaque neovascularization as fractional plasma volume (Vp) and permeability as transfer constant (Ktrans) were analyzed using kinetic modeling. These characteristics were compared between men and women. Men, compared to women, were younger (54 ± 8 vs. 58 ± 8 years, p = 0.01), had higher rate of previous MI (46 vs. 26%, p = 0.005) but lower proportions of metabolic syndrome (37 vs. 59%, p = 0.003). After adjusting for between-gender differences, men were significantly more likely to have LRNC (OR 2.22, 95% CI 1.04-4.89, p = 0.04) and showed significantly larger %LRNC than women (diff = 4.3%, 95% CI 1.6-6.9%, p = 0.002), while %WV, FT, and CA were similar between men and women. There were no statistically significant differences in adventitial and plaque Vp or Ktrans. Men were significantly more likely to have LRNC and had larger LRNC than women. However, men and women showed relatively similar levels of adventitial and plaque neovascularization and permeability.Trial registration: NCT00715273 at ClinicalTrials.gov. Registered 15 July 2008, retrospectively registered.

Low levels of ApoA1 improve risk prediction of type 2 diabetes mellitus.

BACKGROUND: Type 2 diabetes mellitus (T2DM) has reported to be a major public health crisis in China. OBJECTIVE: We examined the incidence of new T2DM over 4 years for association of clinical factors and lipids with development of T2DM in a community-based population. METHODS: We included 923 Chinese subjects who participated in community-organized health checkout in both 2009 and 2013. Health history was collected; physical examination was performed; biochemistry, lipids, and glucose were measured. Of 923, 819 were confirmed without T2DM in 2009 and included in the analysis. Unadjusted and adjusted logistic regression models were used to estimate the effects of clinical factors and biomarkers on the risk of new T2DM. RESULTS: Of 819 subjects without T2DM in 2009, 65 were identified as T2DM in 2013, 8% over 4 years. These 65 subjects, compared with those 754 without new T2DM, were older, more likely to be male and smokers. They had higher body mass index (BMI), fasting glucose, blood pressure and triglycerides, and lower levels of high-density lipoprotein-cholesterol and apolipoprotein A1 (ApoA1). Multivariate logistic regression identified larger BMI (odds ratio [OR] = 1.7; 95% confidence interval [CI], 1.22-2.39, P = .002), higher fasting glucose levels (OR = 4.2, 95% CI, 2.90-6.19, P < .001), and low levels of ApoA1 (OR = 0.51, 95% CI 0.33-0.76, P = .002) were independently associated with new T2DM. Furthermore, receiver operating characteristics curves for multivariate models for new T2DM showed that area under the curve improved from 0.87 to 0.89 when adding ApoA1 to the Framingham Diabetes Risk Scoring Model and from 0.85 to 0.89 when adding ApoA1 to a 4-variable (age, BMI, glucose, and triglycerides) Chinese model. CONCLUSIONS: There is a high incidence of new T2DM at 8% over 4 years among Chinese. Larger BMI, higher glucose levels, and lower levels of ApoA1 are significantly and independently associated with new T2DM. Lower ApoA1 improves the risk prediction of new type 2 diabetes when it was added to the existing risk models.

Niacin Therapy Increases High-Density Lipoprotein Particles and Total Cholesterol Efflux Capacity But Not ABCA1-Specific Cholesterol Efflux in Statin-Treated Subjects.

OBJECTIVE: We investigated relationships between statin and niacin/statin combination therapy and the concentration of high-density lipoprotein particles (HDL-P) and cholesterol efflux capacity, 2 HDL metrics that might better assess cardiovascular disease risk than HDL-cholesterol (HDL-C) levels. APPROACH: In the Carotid Plaque Composition Study, 126 subjects with a history of cardiovascular disease were randomized to atorvastatin or combination therapy (atorvastatin/niacin). At baseline and after 1 year of treatment, the concentration of HDL and its 3 subclasses (small, medium, and large) were quantified by calibrated ion mobility analysis (HDL-PIMA). We also measured total cholesterol efflux from macrophages and ATP-binding cassette transporter A1 (ABCA1)-specific cholesterol efflux capacity. RESULTS: Atorvastatin decreased low-density lipoprotein cholesterol by 39% and raised HDL-C by 11% (P=0.0001) but did not increase HDL-PIMA or macrophage cholesterol efflux. Combination therapy raised HDL-C by 39% (P<0.0001) but increased HDL-PIMA by only 14%. Triglyceride levels did not correlate with HDL-PIMA (P=0.39), in contrast to their strongly negative correlation with HDL-C (P<0.0001). Combination therapy increased macrophage cholesterol efflux capacity (16%, P<0.0001) but not ABCA1-specific efflux. ABCA1-specific cholesterol efflux capacity decreased significantly (P=0.013) in statin-treated subjects, with or without niacin therapy. CONCLUSIONS: Statin therapy increased HDL-C levels but failed to increase HDL-PIMA. It also reduced ABCA1-specific cholesterol efflux capacity. Adding niacin to statin therapy increased HDL-C and macrophage efflux, but had much less effect on HDL-PIMA. It also failed to improve ABCA1-specific efflux, a key cholesterol exporter in macrophages. Our observations raise the possibility that niacin might not target the relevant atheroprotective population of HDL.

HDL-apolipoprotein A-I exchange is independently associated with cholesterol efflux capacity.

HDL is the primary mediator of cholesterol mobilization from the periphery to the liver via reverse cholesterol transport (RCT). A critical first step in this process is the uptake of cholesterol from lipid-loaded macrophages by HDL, a function of HDL inversely associated with prevalent and incident cardiovascular disease. We hypothesized that the dynamic ability of HDL to undergo remodeling and exchange of apoA-I is an important and potentially rate-limiting aspect of RCT. In this study, we investigated the relationship between HDL-apoA-I exchange (HAE) and serum HDL cholesterol (HDL-C) efflux capacity. We compared HAE to the total and ABCA1-specific cholesterol efflux capacity of 77 subjects. We found that HAE was highly correlated with both total (r = 0.69, P < 0.0001) and ABCA1-specific (r = 0.47, P < 0.0001) efflux, and this relationship remained significant after adjustment for HDL-C or apoA-I. Multivariate models of sterol efflux capacity indicated that HAE accounted for approximately 25% of the model variance for both total and ABCA1-specific efflux. We conclude that the ability of HDL to exchange apoA-I and remodel, as measured by HAE, is a significant contributor to serum HDL efflux capacity, independent of HDL-C and apoA-I, indicating that HDL dynamics are an important factor in cholesterol efflux capacity and likely RCT.

Levels of cholesterol in small LDL particles predict atherosclerosis progression and incident CHD in the HDL-Atherosclerosis Treatment Study (HATS).

OBJECTIVE: Test whether angiographically-documented changes in percent stenosis and clinical endpoints (coronary-related deaths, myocardial infarctions, stroke, revascularization for worsening ischemia) in the HDL-Atherosclerosis Treatment Study (HATS) were attributable to specific LDL-subclasses. METHODS: Gradient gel electrophoresis of on-study LDL-subclass cholesterol concentrations were measured in 32 placebo, 33 simvastatin-niacin, 38 antioxidant, and 39 simvastatin-niacin & antioxidant treated participants. The prespecified primary end point was the mean change per patient from the initial arteriogram to the final arteriogram in the percent stenosis caused by the most severe lesion in each of the nine proximal coronary segments. RESULTS: The change in the percent stenosis of the most severe proximal lesions increased in association with higher concentrations of the small LDL subfractions LDL-IIIb (24.2-24.6 nm) and LDL-IVa (23.3-24.1 nm) before (both P = 0.002) and after (P = 0.01 and P = 0.03 respectively) adjustment for treatment group and on-study HDL-cholesterol, LDL-cholesterol, and triglyceride concentrations. The associations appeared specific to lesions with <30% baseline stenosis. When adjusted for age, sex, baseline BMI and cigarette use, the odds for primary clinical endpoints (death from coronary causes, nonfatal myocardial infarction, stroke, or revascularization for worsening ischemia) were significantly greater in subjects with higher on-study LDL-IIIb levels both before (P = 0.01) and after (P = 0.03) adjustment for treatment group and the standard lipid values. CONCLUSIONS: Plasma LDL-IIIb cholesterol concentrations were related to changes in coronary artery stenosis and cardiovascular events in patients with coronary artery disease and low HDL-cholesterol. TRIAL REGISTRATION: ClinicalTrials.gov NCT00000553.

Angiotensin-converting enzyme inhibitors and change in aortic valve calcium.

BACKGROUND: Calcium accumulation in the aortic valve is a hallmark of aortic sclerosis and aortic stenosis. Because lipoproteins, angiotensin-converting enzyme, and angiotensin II colocalize with calcium in aortic valve lesions, we hypothesized an association between angiotensin-converting enzyme inhibitor (ACEI) use and lowered aortic valve calcium (AVC) accumulation, as measured by electron beam computed tomography. METHODS: Rates of change in volumetric AVC scores were determined retrospectively for 123 patients who had undergone 2 serial electron beam computed tomographic scans. The mean (+/-SD) interscan interval was 2.5 (+/-1.7) years; 80 patients did not receive ACEIs and 43 received ACEIs. The relationship of ACEI use to median rates of AVC score change (both unadjusted and adjusted for baseline AVC scores and coronary heart disease risk factors) was determined. We also examined the relationship of ACEI use to the likelihood of and adjusted odds ratio for definite progression (AVC change >2 times the median interscan variability). RESULTS: Unadjusted and adjusted median rates of AVC score change were significantly higher in the no-ACEI group than in the ACEI group (adjusted median AVC changes [95% confidence interval]: relative, 28.7%/y [18.9%-38.5%/y] vs 11.0%/y [-1.9% to 24.0%/y], P = .04; absolute: 25.1/y [19.7-30.5/y] vs 12.2/y [4.5-19.9/y], P = .02). The adjusted odds ratio (95% confidence interval) for definite AVC progression was significantly lower for patients who received ACEIs (0.29 [0.11-0.75], P = .01). CONCLUSIONS: This retrospective study finds a significant association between ACEI use and a lower rate of AVC accumulation. The results support the need for prospective, randomized trials of ACEIs in calcific aortic valve disease.

Tirofiban therapy for patients with acute coronary syndromes and prior coronary artery bypass grafting in the PRISM-PLUS trial.

The role of glycoprotein IIb/IIIa platelet receptor antagonist therapy for patients with an acute coronary syndrome (ACS) and a history of coronary artery bypass grafting (CABG) remains incompletely defined. We examined the outcomes of patients with an ACS and prior CABG who were treated with tirofiban versus placebo among subjects with prior CABG in the Platelet Receptor Inhibition in Ischemic Syndrome Management in Patients Limited by Unstable Signs and Symptoms (PRISM-PLUS) trial. Of 1,570 patients treated with tirofiban plus heparin (n = 773) or heparin alone (n = 797), 231 had prior CABG. Compared with patients without prior CABG, those with prior CABG were more likely to have risk factors for a complicated ACS course, including severe coronary artery disease and heart failure (all p <0.0001), typically had clinical predictors of benefit from tirofiban, such as ST-segment depression (p = 0.01) or a TIMI risk score >or=4 (p <0.001), and were more likely to die or have a myocardial infarction or refractory ischemia at all time points examined (p <0.0001). Among patients with prior CABG, decreases in the incidence of death, myocardial infarction, or refractory ischemia with tirofiban and heparin versus heparin alone were noted at 7 and 30 days (7 days: 16.9% vs 29.0%, p = 0.035; 30 days: 25.0% vs 40.2%, p = 0.015). Trends toward a decrease in death, myocardial infarction, and refractory ischemia with tirofiban and heparin versus heparin alone in the prior CABG subgroup were noted at 48 hours and 180 days (48 hours: 6.5% vs 14.0%, p = 0.09; 180 days: 37.1% vs 48.6%, p = 0.057). Bleeding rates were similar in patients with and without prior CABG. Tirofiban was well tolerated and tended to decrease the considerable risk for ischemic ACS complications in patients with prior CABG.

Predictors of repeat revascularization after nonemergent, first percutaneous coronary intervention in the community.

BACKGROUND: We sought to determine the incidence of and risk factors for repeat revascularization after nonemergent, first percutaneous coronary intervention (PCI) performed in contemporary community practice. METHODS: We analyzed a prospective registry of consecutive patients undergoing isolated PCI in the state of Washington. Multivariate Cox regression analysis was used to determine predictors of repeat revascularization (by PCI or bypass surgery) within 1 year after first PCI. RESULTS: Between January 1, 1999, and December 31, 1999, there were 3571 nonemergent first PCIs, 87.7% of which involved stent placement. Repeat revascularization occurred in 577 (16.2%) patients. Repeat revascularization was predicted by multivessel disease (hazard ratio [HR] 1.36, 95% CI 1.12-1.66), stable versus no angina (HR 1.27, 95% CI 1.03-1.57), and maximum stent length used (per 1 mm longer: HR 1.01, 95% CI 1.002-1.02), while prior myocardial infarction (HR 0.77, 95% CI 0.62-0.96) and creatinine >1.2 mg/dL (HR 0.74, 95% CI 0.56-0.98) were associated with lower risk of repeat revascularization. Diabetes was a significant predictor only when the outcome was limited to revascularization by coronary artery bypass surgery (HR 1.52, 95% CI 1.03-2.23). Although glycoprotein IIb/IIIa inhibitor use was a significant univariate predictor of freedom from early repeat revascularization (within 60 days after first PCI), after controlling for potential confounders, it was no longer significant. CONCLUSIONS: In this contemporary, community-based registry of patients undergoing nonemergent first PCI, clinical practice and outcomes are consistent with evidence from clinical trials and previous controlled studies. Results from controlled studies may reasonably be extrapolated to such a community setting.

Usefulness of aortic valve calcium scores by electron beam computed tomography as a marker for aortic stenosis.

This study was undertaken to determine whether aortic valve calcium (AVC) scores measured by electron beam tomography can identify patients with echocardiographically defined aortic stenosis. Electron beam tomography is increasingly being used to detect coronary artery calcium. AVC can also be measured on electron beam tomographic (EBT) scans obtained to screen for coronary calcium. Whether EBT AVC scores correlate with the presence of aortic stenosis, as assessed by echocardiography, is unknown. Results of this study suggest that AVC scores should be calculated routinely for coronary calcium screening EBT scans, and that patients with Agatston AVC scores above a certain level (e.g., >150) should be referred for echocardiography.

Prediction of native coronary artery disease progression following PTCA or CABG in the Emory Angioplasty Versus Surgery Trial.

BACKGROUND: The natural history of atherosclerosis progression following revascularization procedures (PTCA or CABG) limits the long-term benefits of these procedures and requires continuation of risk management. MATERIAL/METHODS: Of 392 patients with multivessel disease randomized to an initial strategy of PTCA or CABG in the Emory Angioplasty Versus Surgery Trial (EAST), 298 patients (152 PTCA and 146 CABG) completed 3-year angiographic follow-up. Native coronary artery disease progression was defined as lesions with <50% diameter stenosis (%S) at baseline, measured by QCA, that increased at least 10%S to become >or=50%S during the 3-year follow-up. Major ischemic events (new Q-wave myocardial infarction, a large reversible thallium defect or additional revascularization procedures) attributed to these new lesions were determined based on the ECG ischemic changes and/or the details of the coronary anatomy. RESULTS: Of 298 patients, 53 (18%) (15% of PTCA and 21% of CABG) developed at least one significant new native coronary artery lesion. Of 136 patients with events, 19 (14%) had such events due to progression. In multivariate analysis, native coronary disease progression was independently correlated with hypertension (OR=2.4, p=0.03), ST segment depression =1mm on baseline ETT (OR=2.7, p=0.01), and percent of small LDL particles (LDL IIIa-IVb) (OR=1.2 for every 5% increase, p=0.01). CONCLUSIONS: In EAST, the native CAD progression accounted for one in seven major ischemic episodes over a 3-year follow-up. Patients with metabolic atherogenic risk profiles were more likely to have disease progression. These findings indicate the importance of more aggressive risk factor modification following revascularization.

Reproducibility of electron-beam CT measures of aortic valve calcification.

RATIONALE AND OBJECTIVES: The authors performed this study to establish the interscan, interobserver, and intraobserver reproducibility of aortic valve calcification (AVC) measurements obtained with electron-beam computed tomography (CT). MATERIALS AND METHODS: The authors evaluated electron-beam CT scans from all patients who had undergone two serial examinations on the same day as part of a study of coronary artery calcification reproducibility. In patients in whom aortic valve calcium was identified at electron-beam CT, AVC scores were measured with both the Agatston and the volumetric methods, which were developed previously to quantify coronary calcium. RESULTS: Forty-four asymptomatic patients (mean age, 66 years +/- 9) with AVC at electron-beam CT were included in the analyses. AVC score reproducibility was excellent with both the Agatston and the volumetric methods (R2 = 0.99, P = .0001 for both), with median interscan variabilities of 7% and 6.2%, respectively. Interscan reproducibility was similar, whether the analysis included all scans or was restricted to those with scores greater than 10 or greater than 30. For the volumetric method, the median interobserver variability was 5% and the median intraobserver variability was 1%. CONCLUSION: The low interscan, interobserver, and intraobserver variabilities at electron-beam CT suggest that this method should be useful for the noninvasive monitoring of AVC changes over time and for assessing the efficacy of therapies aimed at slowing AVC accumulation.

HMG CoA reductase inhibitor (statin) and aortic valve calcium.

There is no known pharmacological therapy for calcific aortic valvular sclerosis or stenosis. Because leaflet calcification occurs in areas of lipoprotein deposition, we hypothesised that 3-hydroxy-3-methylglutaryl-coenzyme A (HMG COA) reductase inhibitors (statins) might slow aortic valve calcium (AVC) accumulation. We retrospectively identified 65 patients who had undergone two electron-beam computed tomography scans at a mean (SD) interval of 2.5 (1.6) years. 28 (43%) patients were receiving statins. Patients who were treated with statins had a 62-63% lower median rate of AVC accumulation (p=0.006) and 44-49% fewer statin patients had definite AVC progression (p=0.043). These findings suggest that statins may decrease AVC accumulation.