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Effect of statins and non-statin LDL-lowering medications on cardiovascular outcomes in secondary prevention: a meta-analysis of randomized trials.
Koskinas, KC, Siontis, GCM, Piccolo, R, Mavridis, D, Räber, L, Mach, F, Windecker, S
European heart journal. 2018;(14):1172-1180
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Abstract
AIMS: Current evidence on dyslipidaemia management has expanded to novel treatments and very low achieved levels of low-density lipoprotein cholesterol (LDL-C). We sought to compare the clinical impact of more-intensive vs. less-intensive LDL-C lowering by means of statins and currently recommended non-statin medications in secondary prevention. METHODS AND RESULTS We searched Medline, EMBASE, and Cochrane databases for randomized controlled trials of statins, ezetimibe, proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, or bile acid sequestrants with >500 patients followed for ≥1 year. We employed random-effects models using risk ratios (RRs) with 95% confidence intervals (CIs) to compare outcomes. We included 19 trials (15 of statins, 3 of PCSK9 inhibitors, and 1 of ezetimibe) with 152 507 patients randomly assigned to more-intensive (n = 76 678) or less-intensive treatment (n = 75 829). More-intensive treatment was associated with 19% relative risk reduction for the primary outcome, major vascular events (MVEs; RR 0.81, 95% CI 0.77-0.86). Risk reduction was greater across higher baseline levels and greater achieved reductions of LDL-C. The clinical benefit was significant across varying types of more-intensive treatment and was consistent for statins (RR 0.81, 95% CI 0.76-0.86) and non-statin agents (PCSK9 inhibitors and ezetimibe; RR 0.85, 95% CI 0.77-0.94) as active (more-intensive) intervention (P-interaction = 0.38). Each 1.0 mmol/L reduction in LDL-C was associated with 19% relative decrease in MVE. Death, cardiovascular death, myocardial infarction, stroke, and coronary revascularization also favoured more-intensive treatment. CONCLUSION Reduction of MVE is proportional to the magnitude of LDL-C lowering across a broad spectrum of on-treatment levels in secondary prevention. Statin intensification and add-on treatment with PCSK9 inhibitors or ezetimibe are associated with significant reduction of cardiovascular morbidity in this very high-risk population.
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Low-density lipoprotein cholesterol target attainment in patients with stable or acute coronary heart disease in the Asia-Pacific region: results from the Dyslipidemia International Study II.
Poh, KK, Ambegaonkar, B, Baxter, CA, Brudi, P, Buddhari, W, Chiang, FT, Horack, M, Jang, Y, Johnson, B, Lautsch, D, et al
European journal of preventive cardiology. 2018;(18):1950-1963
Abstract
BACKGROUND As mortality due to cardiovascular disease increases throughout the world, accurate data on risk factors such as hyperlipidemia are required. This is lacking in the Asia-Pacific region. DESIGN The observational Dyslipidemia International Study (DYSIS) II was established to quantify the extent of hyperlipidemia in adults with acute and stable coronary heart disease globally. METHODS Patients with stable coronary heart disease or hospitalised with an acute coronary syndrome were enrolled across nine Asia-Pacific countries from July 2013 to October 2014. Lipid-lowering therapy and low-density lipoprotein cholesterol target attainment (<70 mg/dL) were assessed. The acute coronary syndrome cohort was followed up 4 months post-discharge. RESULTS Of the 4592 patients enrolled, 2794 had stable coronary heart disease and 1798 were admitted with an acute coronary syndrome. In the coronary heart disease cohort, the mean low-density lipoprotein cholesterol level was 86.9 mg/dL, with 91.7% using lipid-lowering therapy and 31% achieving low-density lipoprotein cholesterol of less than 70 mg/dL. In the acute coronary syndrome cohort at admission, the corresponding values were 103.2 mg/dL, 63.4% and 23.0%, respectively. Target attainment was significantly higher in lipid-lowering therapy-treated than non-treated patients in each cohort (32.6% vs. 12.9% and 31.1% vs. 9.0%, respectively). Mean atorvastatin-equivalent dosages were low (20 ± 15 and 22 ± 18 mg/day, respectively), with little use of non-statin adjuvants (13.0% and 6.8%, respectively). Low-density lipoprotein cholesterol target attainment had improved by follow-up for the acute coronary syndrome patients, but remained low (41.7%). CONCLUSIONS Many patients in Asia at very high risk of recurrent cardiovascular events had a low-density lipoprotein cholesterol level above the recommended target. Although lipid-lowering therapy was common, it was not used to its full potential.
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Impact of statin-ezetimibe combination on coronary atheroma plaque in patients with and without chronic kidney disease - Sub-analysis of PRECISE-IVUS trial.
Fujisue, K, Nagamatsu, S, Shimomura, H, Yamashita, T, Nakao, K, Nakamura, S, Ishihara, M, Matsui, K, Yamamoto, N, Koide, S, et al
International journal of cardiology. 2018;:23-26
Abstract
BACKGROUND Chronic kidney disease (CKD) deteriorates the prognosis of patients undergoing percutaneous coronary intervention (PCI). Because coronary artery disease (CAD) is the major cause of death in CKD patients, cardiovascular risk reduction has been clinically important in CKD. We hypothesized intensive lipid-lowering with statin/ezetimibe attenuated coronary atherosclerotic development even in patients with CKD. METHODS In the prospective, randomized, controlled, multicenter PRECISE-IVUS trial, 246 patients undergoing intravascular ultrasound (IVUS)-guided PCI were randomly assigned to receive atorvastatin/ezetimibe combination or atorvastatin alone (the dosage of atorvastatin was up-titrated to achieve the level of low-density lipoprotein cholesterol < 70 mg/dL). Serial volumetric IVUS findings obtained at baseline and 9-12 month follow-up to quantify the coronary plaque response in 202 patients were compared stratified by the presence or absence of CKD. RESULTS CKD was observed in 52 patients (26%) among 202 enrolled patients. Compared with the non-CKD group, the CKD group was significantly older (71.5 ± 8.6 years vs. 64.4 ± 9.6 years, P < 0.001) with similar prevalence of comorbid coronary risk factors and lipid profiles. Similar to the non-CKD group (-1.4 [-2.8 to -0.1]% vs. -0.2 [-1.7 to 1.0]%, P = 0.002), the atorvastatin/ezetimibe combination significantly reduced ∆PAV compared with atorvastatin alone even in the CKD group (-2.6 [-5.6 to -0.4]% vs. -0.9 [-2.4 to 0.2]%, P = 0.04). CONCLUSIONS As with non-CKD, intensive lipid-lowering therapy with atorvastatin/ezetimibe demonstrated stronger coronary plaque regression effect even in patients with CKD compared with atorvastatin monotherapy. TRIAL REGISTRATION NCT01043380 (ClinicalTrials.gov).
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On-treatment lipid profiles to predict the cardiovascular outcomes in ASCVD patients comorbid with chronic kidney disease - The multi-center T-SPARCLE registry study.
Ho, LT, Lin, FJ, Tseng, WK, Yin, WH, Wu, YW, Li, YH, Yeh, HI, Chen, JW, Wu, CC, ,
Journal of the Formosan Medical Association = Taiwan yi zhi. 2018;(9):814-824
Abstract
BACKGROUND The aim of this study is to determine the relationship between the on-treatment lipid profiles and the CV events in CKD and non-CKD population. METHOD This study was a multi-center observational registry, the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry. This study follows up patients with CV diseases in Taiwan who have secondary prevention therapies. The primary outcome is the time of first occurrence of a major adverse cardiac events (MACEs). RESULT 5388 patients with ASCVD were included and 1478 (27.4%) had CKD without dialysis. CKD patients had higher TG and lower LDL-C levels. The incidence of recurrent MACEs per 1000 person-years in CKD patients was 19.5 (95% CI 15.5-24.9), compared with 9.1 (95% CI 7.4-11.1) in non-CKD patients. In patients with statin therapy, there were no differences in MACE risk between each level of on-treatment LDL-C, TG and HDL-C level. Higher on-treatment non-HDL-C level was a significant predictor for higher MACE risk in patients without CKD, and borderline significant in CKD patients under statin therapy. Heart failure history was also associated with higher MACE risk in both group. Lower body mass index (BMI < 23 kg/m2) was associated with higher MACE risk in CKD patients. CONCLUSION In ASCVD patients, on-treatment LDL-C was not a good CV outcome predictor. Instead, on-treatment non-HDL-C was a better predictor. Heart failure history was also associated with higher MACE risk in both group of patients. Lower BMI (<23 kg/m2) was associated with higher recurrent MACE risk in CKD patients.
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Combination Lipid-Lowering Therapies for the Prevention of Recurrent Cardiovascular Events.
Lee, S, Cannon, CP
Current cardiology reports. 2018;(7):55
Abstract
PURPOSE OF REVIEW There has been confusion following the 2013 American College of Cardiology/American Heart Association (ACC/AHA) Lipid guidelines on the role of non-statin medications for cardiovascular prevention. RECENT FINDINGS Several recent large trials have also now shown that lowering LDL with non-statins reduces cardiovascular events. In ASCVD patients on statins, adding ezetimibe or a PCSK9 inhibitor led to reductions in CV events in the IMPROVE IT, FOURIER, and most recently the ODYSSEY-OUTCOMES trials. Additional novel therapies reducing LDL and other atherogenic lipoproteins are in development during this exciting time in this field. With recent evidence, the 2017 ACC Expert Consensus Decision pathway calls for initial therapy with statins, monitoring LDL levels, and then adding ezetimibe and/or PCSK9 inhibitors to further lower LDL-C to targets based on the patient's risk.
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Beneficial effects of walnut consumption on human health: role of micronutrients.
Ros, E, Izquierdo-Pulido, M, Sala-Vila, A
Current opinion in clinical nutrition and metabolic care. 2018;(6):498-504
Abstract
PURPOSE OF REVIEW Nuts in general and walnuts in particular are in the limelight for the association of their consumption with improved health outcomes. Walnuts have an optimal composition in bioactive nutrients and recent clinical and experimental studies have uncovered a number of beneficial effects of walnut micronutrients, working in isolation or in concert, on metabolic pathways and clinical outcomes that make this review timely and relevant. RECENT FINDINGS Alpha-linolenic acid, a critical walnut component, is metabolized into bioactive oxylipins, has been shown to protect microglial cells from inflammation, and is associated with lower fatal myocardial infarction rates through a putative antiarrhythmic effect. Phytosterols relate to the cholesterol-lowering effect of nut consumption. Nonsodium minerals are associated with better cardiometabolic health. Walnut phytomelatonin has anticancer effects that are shared by the main walnut polyphenols and their metabolites, ellagitannins and urolithins, respectively. SUMMARY This review highlights new evidence on the health-promoting properties of walnuts and their main micronutrient components. The conclusion is that walnuts are optimal healthful foods.
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Comparative Effectiveness of Inclisiran 100, 300, and 500 mg in a Population with Hyperlipidemia: A Network Meta-Analysis of Randomized Controlled Trials.
Wang, Y, Wang, J, Wang, S
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2018;(4):271-282
Abstract
BACKGROUND To our knowledge, inclisiran was the first agent composed of small interfering RNAs (siRNAs) to be preliminarily used to reduce proatherogenic lipoprotein cholesterol levels. Inclisiran was evaluated in large clinical trials but did not receive government approval. The ability of inclisiran to reduce low-density lipoprotein cholesterol (LDL-C) greatly improved its chances of becoming a novel therapeutic option for patients with hyperlipidemia. OBJECTIVE Our goal was to summarize the preliminary effectiveness and safety data for inclisiran. METHODS We conducted a comprehensive search of PubMed, Scopus, Web of Science, the OVID EMB Reviews database, and Clinical Trials with the keyword "inclisiran" to find all related randomized controlled trials (RCTs). Five recently published RCTs involving 583 adults aged 18-65 years with hyperlipidemia were included in the analysis. RESULTS Subgroup analysis suggested that inclisiran 100 mg (standard mean difference [SMD] - 2.09; 95% confidence interval [CI] - 2.51 to - 1.66; p < 0.05), 300 mg (SMD - 2.74; 95% CI - 3.61 to - 1.87; p < 0.05), and 500 mg (SMD - 2.21; 95% CI - 2.62 to - 1.80; p < 0.05) significantly (p < 0.05) reduced LDL-C and total cholesterol even though pooled analysis showed no LDL-C-lowering effect (SMD 0.15; 95% CI - 0.34 to 0.04; p = 0.116). Compared with patients receiving placebo, pooled and subgroup analysis of patients receiving inclisiran showed no favorable changes in triglycerides or high-density lipoprotein cholesterol (p > 0.05). The most commonly reported adverse events were musculoskeletal pain, nasopharyngitis, headache, and elevated C-reactive protein (CRP), none of which were significant (p > 0.05). CONCLUSIONS To date, inclisiran has been effective in treating hyperlipidemia. Major adverse events were not identified, although other possible adverse events may be discovered with more RCTs and extensive long-term follow-up.
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ADCY9 Genetic Variants and Cardiovascular Outcomes With Evacetrapib in Patients With High-Risk Vascular Disease: A Nested Case-Control Study.
Nissen, SE, Pillai, SG, Nicholls, SJ, Wolski, K, Riesmeyer, JS, Weerakkody, GJ, Foster, WM, McErlean, E, Li, L, Bhatnagar, P, et al
JAMA cardiology. 2018;(5):401-408
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Abstract
IMPORTANCE A pharmacogenetic analysis of dalcetrapib, a cholesteryl ester transfer protein inhibitor, reported an association between a single-nucleotide polymorphism (SNP) in the ADCY9 gene (rs1967309) and reduction in major adverse cardiovascular events despite a neutral result for the overall trial. OBJECTIVE To determine whether the association between the SNP in the ADCY9 gene and a reduction in major adverse cardiovascular events could be replicated for another cholesteryl ester transfer protein inhibitor, evacetrapib, in patients with high-risk vascular disease. DESIGN, SETTING, AND PARTICIPANTS A nested case-control study examining the rs1967309 SNP in 1427 cases and 1532 matched controls selected from the 12 092-patient Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition with Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial, a randomized, double-blind, placebo-controlled phase 3 trial conducted in patients with high-risk vascular disease randomized from October 2012 through December 2013. The genotyping was conducted from January 2017 to March 2017, and the data analyses were conducted from July 2017 to November 2017. EXPOSURES Evacetrapib, 130 mg, or matching placebo. MAIN OUTCOMES AND MEASURES The primary analyses used a conditional logistic regression model to assess the odds ratio (OR) for major adverse cardiovascular events for evacetrapib compared with placebo for each genotype. The basic model included adjustment for age, sex, and the top 5 principal components. An additional model included cardiovascular risk factors to adjust for potential bias in selecting control patients. The primary major adverse cardiovascular event end point was the composite of death from cardiovascular causes, myocardial infarction, stroke, coronary revascularization, or hospitalization for unstable angina. RESULTS For patients with the AA genotype reported to demonstrate a beneficial effect from dalcetrapib, the OR for evacetrapib compared with placebo was 0.88 (95% CI, 0.69-1.12). For patients with the AG genotype, the OR was 1.04 (95% CI, 0.90-1.21). For patients with the GG genotype reported to show evidence for a harmful effect from dalcetrapib, the OR for evacetrapib was 1.18 (95% CI, 0.98-1.41). The interaction P value among the 3 genotypes was P = .17 and the trend P value was P = .06. When adjusted for cardiovascular risk factors, the OR for evacetrapib was 0.93 (95% CI, 0.73-1.19) for the AA genotype, 1.05 (95% CI, 0.91-1.22) for the AG genotype, and 1.02 (95% CI 0.85-1.24) for the GG genotype; interaction P = .71 and trend P = .59. CONCLUSIONS AND RELEVANCE Pharmacogenetic analysis did not show a significant association between the ADCY9 SNP (rs1967309) and cardiovascular benefit or harm for the cholesteryl ester transfer protein inhibitor evacetrapib.
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Cholesterol metabolism in humans: a review of methods and comparison of results.
Millar, JS, Cuchel, M
Current opinion in lipidology. 2018;(1):1-9
Abstract
PURPOSE OF REVIEW Cholesterol metabolism has been the object of intense investigation for decades. This review focuses on classical and novel methods assessing in vivo cholesterol metabolism in humans. Two factors have fueled cholesterol metabolism studies in the last few years: the renewed interest in the study of reverse cholesterol transport (RCT) as an atheroprotective mechanism and the importance of the gut microbiome in affecting cholesterol metabolism. RECENT FINDINGS Recent applications of these methods have spanned from the assessment of the effect on cholesterol synthesis, absorption or excretion of drugs (such as ezetimibe, PCSK9 inhibitors and plant sterols) and the gut microbiome to the more complex assessment of transintestinal cholesterol excretion (TICE) and RCT. SUMMARY These methods continue to be a valuable tool to answer novel questions and investigate the complexity of in-vivo cholesterol metabolism.
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PCSK9 Inhibitors: Mechanisms of Action, Metabolic Effects, and Clinical Outcomes.
Hess, CN, Low Wang, CC, Hiatt, WR
Annual review of medicine. 2018;:133-145
Abstract
Atherosclerotic cardiovascular disease (ASCVD) is associated with significant morbidity and mortality worldwide. Increased serum levels of low-density lipoprotein cholesterol (LDL-C) are an independent risk factor for ASCVD, and clinical trial data have shown that lowering LDL-C generally reduces cardiovascular risk. Until recently, 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins) have been the main therapy for lowering LDL-C. However, some statin-treated patients have persistently elevated residual cardiovascular risk due to inadequate lowering of LDL-C levels or non-LDL-related dyslipidemia. In addition, adverse effects of statins may limit their tolerability and therefore the ability to attain effective doses in some patients. A new class of drugs that inhibit proprotein convertase subtilisin-kexin type 9 (PCSK9) has been developed to treat hyperlipidemia. This review discusses the history and mechanism of action of PCSK9 inhibitors, their metabolic effects, and clinical outcomes associated with these medications, highlighting recent large cardiovascular outcome trials investigating these therapies.