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Lp(a): Addressing a Target for Cardiovascular Disease Prevention.
Vasquez, N, Joshi, PH
Current cardiology reports. 2019;(9):102
Abstract
PURPOSE OF REVIEW To review the current recommendations for lipoprotein(a) (Lp(a)) screening, the evidence behind the thresholds for increased cardiovascular disease (CVD) risk, and the available data supporting Lp(a) lowering. RECENT FINDINGS Lp(a) is almost entirely genetically determined and has an independent causal association with CVD. Measurement of Lp(a) is challenging given the structural heterogeneity of apolipoprotein a (apo(a)), for which isoform-insensitive immunoassays should be used. Current guidelines do not recommend treatment to lower Lp(a) but rather focus on intensified preventive measures including low-density lipoprotein cholesterol (LDL-C) lowering in patients with high Lp(a). Evidence suggests that levels higher than 50 mg/dL (125 nmol/L) identify significantly increased CVD risk. Mendelian randomization studies suggest that in order to have a clinically significant reduction in coronary heart disease, Lp(a) levels should be reduced by at least 60-70 mg/dL to attain a significant benefit. Ongoing studies of targeted therapy with antisense oligonucleotides (ASO) have shown promising reductions in Lp(a) up to 80%, but a cardiovascular outcomes trial is needed. There is unquestionably an increased risk for CVD in patients with elevated Lp(a); however, measurement assay issues and the lack of Lp(a)-targeted therapies with proven outcome reduction limit the clinical utility of this important risk factor. Available evidence suggesting specific thresholds for clinically significant CVD risk are based on European or Caucasian populations, not accounting for important racial differences. Novel Lp(a)-targeted emerging therapies may need to account for an expected reduction of at least 60-70 mg/dL to achieve a clinically significant benefit.
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Lipoprotein(a): An independent, genetic, and causal factor for cardiovascular disease and acute myocardial infarction.
Enas, EA, Varkey, B, Dharmarajan, TS, Pare, G, Bahl, VK
Indian heart journal. 2019;(2):99-112
Abstract
Lipoprotein(a) [Lp(a)] is a circulating lipoprotein, and its level is largely determined by variation in the Lp(a) gene (LPA) locus encoding apo(a). Genetic variation in the LPA gene that increases Lp(a) level also increases coronary artery disease (CAD) risk, suggesting that Lp(a) is a causal factor for CAD risk. Lp(a) is the preferential lipoprotein carrier for oxidized phospholipids (OxPL), a proatherogenic and proinflammatory biomarker. Lp(a) adversely affects endothelial function, inflammation, oxidative stress, fibrinolysis, and plaque stability, leading to accelerated atherothrombosis and premature CAD. The INTER-HEART Study has established the usefulness of Lp(a) in assessing the risk of acute myocardial infarction in ethnically diverse populations with South Asians having the highest risk and population attributable risk. The 2018 Cholesterol Clinical Practice Guideline have recognized elevated Lp(a) as an atherosclerotic cardiovascular disease risk enhancer for initiating or intensifying statin therapy.
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Prognostic value of elevated lipoprotein(a) in patients with acute coronary syndromes.
Gencer, B, Rigamonti, F, Nanchen, D, Vuilleumier, N, Kern, I, Aghlmandi, S, Klingenberg, R, Räber, L, Auer, R, Carballo, D, et al
European journal of clinical investigation. 2019;(7):e13117
Abstract
BACKGROUND Minimal lipoprotein(a) [Lp(a)] target values are advocated for high-risk cardiovascular patients. We investigated the prognostic value of Lp(a) in the acute setting of patients with acute coronary syndromes (ACS). MATERIALS AND METHODS Plasma levels of Lp(a) were collected at time of angiography from 1711 patients hospitalized for ACS in a multicentre Swiss prospective cohort. Associations between elevated Lp(a) ≥30 mg/dL (cut-off corresponding to the 75th percentile of the assay) or Lp(a) tertiles at baseline, and major adverse cardiovascular events (MACE) at 1 year, defined as a composite of cardiac death, myocardial infarction or stroke, were assessed using hazard ratios (HR) and 95% confidence intervals (CI) adjusting for traditional cardiovascular risk factors (age, sex, smoking, diabetes, hypertension, low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C] and triglycerides. RESULTS Lp(a) levels range between 2.5 and 132 mg/dL with a median value of 6 mg/dL and a mean value of 14.2 mg/dL. A total of 276 patients (23.0%) had Lp(a) plasma levels ≥30 mg/dL. Patients with elevated Lp(a) were more likely to be of female gender and to have higher levels of total cholesterol, LDL-C, HDL-C and triglycerides. Higher Lp(a) was associated with failure to reach the LDL-C target <1.8 mmol/L at 1 year (HR 1.71, 95% CI 1.13-2.58, P = 0.01). No association was found between elevated Lp(a) and MACE at 1 year (HR 1.05, 95% CI 0.64-1.73), nor for Lp(a) tertiles (HR 0.82, 95% CI 0.52-1.28, P > 0.20) or standardized continuous variables (0.98, 95% CI 0.82-1.19 for each increase of standard deviation). CONCLUSIONS Our real-world data suggest high Lp(a) levels at time of angiography are not predictive for cardiovascular outcomes in patients otherwise medically well controlled, but might be useful to identify patients who would not be on LDL-C targets 1 year after ACS.
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Lipoprotein(a), PCSK9 Inhibition, and Cardiovascular Risk.
O'Donoghue, ML, Fazio, S, Giugliano, RP, Stroes, ESG, Kanevsky, E, Gouni-Berthold, I, Im, K, Lira Pineda, A, Wasserman, SM, Češka, R, et al
Circulation. 2019;(12):1483-1492
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Abstract
BACKGROUND Lipoprotein(a) [Lp(a)] may play a causal role in atherosclerosis. PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors have been shown to significantly reduce plasma Lp(a) concentration. However, the relationship between Lp(a) levels, PCSK9 inhibition, and cardiovascular risk reduction remains undefined. METHODS Lp(a) was measured in 25 096 patients in the FOURIER trial (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), a randomized trial of evolocumab versus placebo in patients with established atherosclerotic cardiovascular disease (median follow-up, 2.2 years). Cox models were used to assess the independent prognostic value of Lp(a) and the efficacy of evolocumab for coronary risk reduction by baseline Lp(a) concentration. RESULTS The median (interquartile range) baseline Lp(a) concentration was 37 (13-165) nmol/L. In the placebo arm, patients with baseline Lp(a) in the highest quartile had a higher risk of coronary heart disease death, myocardial infarction, or urgent revascularization (adjusted hazard ratio quartile 4: quartile 1, 1.22; 95% CI, 1.01-1.48) independent of low-density lipoprotein cholesterol. At 48 weeks, evolocumab significantly reduced Lp(a) by a median (interquartile range) of 26.9% (6.2%-46.7%). The percent change in Lp(a) and low-density lipoprotein cholesterol at 48 weeks in patients taking evolocumab was moderately positively correlated ( r=0.37; 95% CI, 0.36-0.39; P<0.001). Evolocumab reduced the risk of coronary heart disease death, myocardial infarction, or urgent revascularization by 23% (hazard ratio, 0.77; 95% CI, 0.67-0.88) in patients with a baseline Lp(a) >median, and by 7% (hazard ratio, 0.93; 95% CI, 0.80-1.08; P interaction=0.07) in those ≤median. Coupled with the higher baseline risk, the absolute risk reductions, and number needed to treat over 3 years were 2.49% and 40 versus 0.95% and 105, respectively. CONCLUSIONS Higher levels of Lp(a) are associated with an increased risk of cardiovascular events in patients with established cardiovascular disease irrespective of low-density lipoprotein cholesterol. Evolocumab significantly reduced Lp(a) levels, and patients with higher baseline Lp(a) levels experienced greater absolute reductions in Lp(a) and tended to derive greater coronary benefit from PCSK9 inhibition. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT01764633.
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HEART UK consensus statement on Lipoprotein(a): A call to action.
Cegla, J, Neely, RDG, France, M, Ferns, G, Byrne, CD, Halcox, J, Datta, D, Capps, N, Shoulders, C, Qureshi, N, et al
Atherosclerosis. 2019;:62-70
Abstract
Lipoprotein(a), Lp(a), is a modified atherogenic low-density lipoprotein particle that contains apolipoprotein(a). Its levels are highly heritable and variable in the population. This consensus statement by HEART UK is based on the evidence that Lp(a) is an independent cardiovascular disease (CVD) risk factor, provides recommendations for its measurement in clinical practice and reviews current and emerging therapeutic strategies to reduce CVD risk. Ten statements summarise the most salient points for practitioners and patients with high Lp(a). HEART UK recommends that Lp(a) is measured in adults as follows: 1) those with a personal or family history of premature atherosclerotic CVD; 2) those with first-degree relatives who have Lp(a) levels >200 nmol/l; 3) patients with familial hypercholesterolemia; 4) patients with calcific aortic valve stenosis and 5) those with borderline (but <15%) 10-year risk of a cardiovascular event. The management of patients with raised Lp(a) levels should include: 1) reducing overall atherosclerotic risk; 2) controlling dyslipidemia with a desirable non-HDL-cholesterol level of <100 mg/dl (2.5 mmol/l) and 3) consideration of lipoprotein apheresis.
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6.
Current Role of Lipoprotein Apheresis.
Thompson, G, Parhofer, KG
Current atherosclerosis reports. 2019;(7):26
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Abstract
PURPOSE OF REVIEW Lipoprotein apheresis is a very efficient but time-consuming and expensive method of lowering levels of low-density lipoprotein cholesterol, lipoprotein(a)) and other apoB containing lipoproteins, including triglyceride-rich lipoproteins. First introduced almost 45 years ago, it has long been a therapy of "last resort" for dyslipidaemias that cannot otherwise be managed. In recent years new, very potent lipid-lowering drugs have been developed and the purpose of this review is to define the role of lipoprotein apheresis in the current setting. RECENT FINDINGS Lipoprotein apheresis still plays an important role in managing patients with homozygous FH and some patients with other forms of hypercholesterolaemia and cardiovascular disease. In particular, patients not achieving treatment goals despite modern lipid-lowering drugs, either because these are not tolerated or the response is insufficient. Recently, lipoprotein(a) has emerged as an important cardiovascular risk factor and lipoprotein apheresis has been used to decrease lipoprotein(a) concentrations in patients with marked elevations and cardiovascular disease. However, there is considerable heterogeneity concerning the recommendations by scientific bodies as to which patient groups should be treated with lipoprotein apheresis. Lipoprotein apheresis remains an important tool for the management of patients with severe drug-resistant dyslipidaemias, especially those with homozygous FH.
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Lipoprotein apheresis efficacy, challenges and outcomes: A descriptive analysis from the UK Lipoprotein Apheresis Registry, 1989-2017.
Pottle, A, Thompson, G, Barbir, M, Bayly, G, Cegla, J, Cramb, R, Dawson, T, Eatough, R, Kale, V, Neuwirth, C, et al
Atherosclerosis. 2019;:44-51
Abstract
BACKGROUND AND AIMS In 2008, the National Institute of Health and Care Excellence in the UK recommended that patients undergoing lipoprotein apheresis (LA) should be included in an anonymised registry. The UK Lipoprotein Apheresis Registry was subsequently established in 2011. METHODS Between 2011 and 2017, data was entered retrospectively and prospectively by seven LA centres in the UK for 151 patients. Twenty-two patients were involved in a research study and were therefore excluded from the analysis. Observational data was analysed for the remaining 129 patients. RESULTS Most patients had heterozygous familial hypercholesterolaemia (HeFH) (45.0%); 23.3% had homozygous FH (HoFH); 7.8% had hyper-lipoproteinaemia (a) (Lp(a)) and 24.0% had other forms of dyslipidaemia. Detailed treatment data is available for 63 patients relating to 348 years of LA treatment. The number of years of treatment per patient ranged from 1 to 15. The mean reduction in interval mean LDL-C from the pre-procedure baseline was 43.14%. The mean reduction in interval mean Lp(a) from baseline was 37.95%. The registry data also shows a 62.5% reduction in major adverse cardiovascular events (MACE) between the 2 years prior to, and the first 2 years following introduction of LA. CONCLUSIONS The data generated by the UK Lipoprotein Apheresis Registry demonstrates that LA is a very efficient method of reducing LDL-C and Lp(a) and lowers the incidence rate of MACE. LA is an important tool in the management of selected patients with HoFH and drug-resistant dyslipidaemias.
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Elevated lipoprotein (a) levels are associated with the acute myocardial infarction in patients with normal low-density lipoprotein cholesterol levels.
Cai, G, Huang, Z, Zhang, B, Yu, L, Li, L
Bioscience reports. 2019;(4)
Abstract
Elevated lipoprotein (a) [Lp(a)] and coronary artery disease (CAD) risk has been renewed interested in recent years. However, the association between Lp(a) and acute myocardial infarction (AMI) risk in patients with normal low-density lipoprotein cholesterol (LDL-C) levels has yet to been established. A hospital-based observational study including 558 AMI patients and 1959 controls was conducted. Lp(a) level was significantly higher in AMI patients with normal LDL-C levels than that in non-CAD group (median: 134.5 mg/l vs 108 mg/l, P<0.001). According to Lp(a) quartiles (Q1, <51 mg/l; Q2, 51-108 mg/l; Q3, 108-215 mg/l; Q4, ≥215 mg/l), the incidence of AMI increased with the elevated Lp(a) quartiles (P<0.001 and P for trend<0.001). Logistic regression analysis suggested that patients with Q3 and Q4 of Lp(a) values had 1.666 (95%CI = 1.230-2.257, P<0.001) and 1.769 (95%CI = 1.305-2.398, P< 0.001) folds of AMI risk compared with patients with Q1, after adjusting for traditional confounders. Subgroup analyses stratified by gender and age showed that the association only existed in male and late-onset subgroups. In addition, we analyzed the association of Lp(a) with AMI risk in different cut-off values (cut-off 1 = 170 mg/l, cut-off 2 = 300 mg/l). A total of 873 (34.68%) and 432 (17.16%) participants were measured to have higher Lp(a) levels according to cut-off 1 and cut-off 2, respectively. Participants with high Lp(a) levels had 1.418- (cut-off1, 95%CI = 1.150-1.748, P<0.001) and 1.521- (cut-off 2, 95%CI = 1.179-1.963, P< 0.001) folds of AMI risk compared with patients with low Lp(a) levels. The present large-scale study revealed that elevated Lp(a) levels were associated with increased AMI risk in Chinese population with normal LDL-C levels.
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A Meta-Analysis of the Effect of PCSK9-Monoclonal Antibodies on Circulating Lipoprotein (a) Levels.
Cao, YX, Liu, HH, Li, S, Li, JJ
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2019;(1):87-97
Abstract
BACKGROUND Lipoprotein (a) [Lp(a)] is an atherogenic lipoprotein. While no effective therapy for Lp(a) is currently available, recently, several pooled analyses with small sample sizes have suggested that proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9-mAbs) could reduce circulating Lp(a) levels. This meta-analysis was performed to comprehensively investigate the efficacy of PCSK9-mAbs with respect to serum Lp(a) concentrations. METHODS PubMed, MEDLINE, Embase, ClinicalTrials.gov, Cochrane CENTRAL, Web of Science and recent conferences up to July 2018 were searched. Randomized clinical trials evaluating the effect of PCSK9-mAbs and control treatment on plasma Lp(a) concentrations were included. Mean differences and odds ratios with 95% confidence intervals (CIs) were used. RESULTS Twenty-seven randomized clinical trials with a total of 11,864 participants were included. PCSK9-mAbs showed a significant efficacy in reducing Lp(a) (- 21.9%, 95% CI - 24.3 to - 19.5), irrespective of PCSK9-mAb types, treatment duration, participant characteristics, treatment methods, differences of control treatment, baseline Lp(a) levels, and test methods. The greatest reduction was achieved with 150 mg alirocumab biweekly (- 24.6%, 95% CI - 28.0 to - 21.2) and 140 mg evolocumab monthly (- 26.8%, 95% CI - 31.6 to - 21.9). Meta-regression analyses found that the more intense low-density lipoprotein cholesterol levels declined during PCSK9-mAb treatment, the greater the reduction in Lp(a) levels. Safety was in accordance with previous reports. CONCLUSIONS The results of this analysis suggested that PCSK9-mAbs could significantly reduce circulating Lp(a) levels. Long-term studies may be needed to confirm the effect of PCSK9-mAbs on Lp(a) in the future.
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Lipoprotein(a) reductions from PCSK9 inhibition and major adverse cardiovascular events: Pooled analysis of alirocumab phase 3 trials.
Ray, KK, Vallejo-Vaz, AJ, Ginsberg, HN, Davidson, MH, Louie, MJ, Bujas-Bobanovic, M, Minini, P, Eckel, RH, Cannon, CP
Atherosclerosis. 2019;:194-202
Abstract
BACKGROUND AND AIMS Elevated lipoprotein(a) [Lp(a)] levels are considered a causal factor for cardiovascular disease. In phase 3 ODYSSEY trials, alirocumab reduced levels of low-density lipoprotein cholesterol (LDL-C) and Lp(a), with concomitant reductions in the risk of major adverse cardiovascular events (MACE). We assessed whether lower on-study and greater percentage reductions in Lp(a) are associated with a lower risk of MACE. METHODS Post-hoc analysis of data pooled from 10 phase 3 ODYSSEY trials comparing alirocumab with control (placebo or ezetimibe) in patients (n = 4983) with cardiovascular disease and/or risk factors, and hypercholesterolemia despite statin/other lipid-lowering therapies. RESULTS Median (Q1, Q3) baseline Lp(a) levels were 23.5 (8.0, 67.0) mg/dL. Median Lp(a) changes from baseline with alirocumab were -25.6% vs. -2.5% with placebo (absolute reductions 6.8 vs. 0.5 mg/dL) in placebo-controlled trials, and -21.4% vs. 0.0% with ezetimibe (4.5 vs. 0.0 mg/dL) in ezetimibe-controlled trials. During follow-up (6699 patient-years), 104 patients experienced MACE. A 12% relative risk reduction in MACE per 25% reduction in Lp(a) (p=0.0254) was no longer significant after adjustment for LDL-C changes: hazard ratio per 25% reduction: 0.89 (95% confidence interval, 0.79-1.01; p=0.0780). In subgroup analysis, the association between Lp(a) reduction and MACE remained significant in a fully adjusted model among participants with baseline Lp(a) ≥50 mg/dL (p-interaction vs. Lp(a) < 50 mg/dL: 0.0549). CONCLUSIONS In this population, Lp(a) reductions were not significantly associated with MACE independently of LDL-C reductions. Reducing the risk of MACE by targeting Lp(a) may require greater reductions in Lp(a) with more potent therapies and/or higher initial Lp(a) levels.