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Influence of lipoproteins and antiplatelet agents on vein graft patency 1 year after coronary artery bypass grafting.
Zhu, J, Zhu, Y, Zhang, M, Xue, Q, Hu, J, Liu, H, Wang, R, Wang, X, Zhao, Q
The Journal of thoracic and cardiovascular surgery. 2022;(3):1030-1039.e4
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Abstract
OBJECTIVE It remains unclear whether aggressive low-density lipoprotein cholesterol (LDL-C) management (<1.8 mmol/L) can slow the process of vein graft stenosis. This study aimed to explore the impact of baseline LDL-C levels on vein graft patency in patients on ticagrelor with or without aspirin 1 year after coronary artery bypass grafting (CABG). METHODS This was a post hoc analysis of the DACAB (Different Antiplatelet Therapy Strategy After Coronary Artery Bypass Graft Surgery) trial (NCT02201771), a randomized controlled trial (ticagrelor + aspirin or ticagrelor vs aspirin) of patients undergoing CABG in China. The study subjects were stratified as LDL-low (baseline LDL-C <1.8 mmol/L, 148 patients with 430 vein grafts) versus LDL-high (baseline LDL-C ≥1.8 mmol/L, 352 patients with 1030 vein grafts). The primary outcome was the 1-year vein graft patency (Fitzgibbon grade A) assessed by coronary computed tomographic angiography or coronary angiography. RESULTS Baseline/1-year LDL-C were 1.4/1.6 and 2.6/2.4 mmol/L in the LDL-low and LDL-high subgroups, respectively. Regardless of antiplatelet regimen, no significant inter-subgroup difference was observed for 1-year graft patency (LDL-low: 83.8% [359/430 grafts]; LDL-high: 82.3% [848/1030 grafts]; adjusted OR for non-patency [ORadj], 0.96; 95% confidence interval [CI], 0.62-1.50, P = .857). For both subgroups, the 1-year graft patency rates were greater with ticagrelor + aspirin versus aspirin (LDL-low: ORadj, 0.41; 95% CI, 0.17-0.97; LDL-high: ORadj, 0.38; 95% CI, 0.20-0.71; inter P = .679). CONCLUSIONS In general, baseline LDL-C is not associated with 1-year vein graft patency after CABG. Regardless of the baseline LDL-C levels, ticagrelor + aspirin was superior to aspirin alone in maintaining vein graft patency. The primary factor causing early vein graft disease might not be atherosclerosis but thrombosis.
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Clinical Efficacy and Safety of Alirocumab After Acute Coronary Syndrome According to Achieved Level of Low-Density Lipoprotein Cholesterol: A Propensity Score-Matched Analysis of the ODYSSEY OUTCOMES Trial.
Schwartz, GG, Gabriel Steg, P, Bhatt, DL, Bittner, VA, Diaz, R, Goodman, SG, Jukema, JW, Kim, YU, Li, QH, Manvelian, G, et al
Circulation. 2021;(11):1109-1122
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BACKGROUND Recent international guidelines have lowered recommended target levels of low-density lipoprotein cholesterol (LDL-C) for patients at very high risk for major adverse cardiovascular events (MACE). However, uncertainty persists whether additional benefit results from achieved LDL-C levels below the conventional targets. Inferences from previous analyses are limited because patients who achieve lower versus higher LDL-C on lipid-lowering therapy differ in other characteristics prognostic for MACE and because few achieved very low LDL-C levels. To overcome these limitations, we performed a propensity score-matching analysis of the ODYSSEY OUTCOMES trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) which compared alirocumab with placebo in 18 924 patients with recent acute coronary syndrome receiving intensive or maximum-tolerated statin treatment. METHODS Patients on alirocumab were classified in prespecified strata of LDL-C achieved at 4 months of treatment: <25 (n=3357), 25 to 50 (n=3692), or >50 mg/dL (n=2197). For each stratum, MACE (coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) after month 4 was compared in patients receiving placebo with similar baseline characteristics and adherence by using 1:1 propensity score matching. RESULTS Across achieved LDL-C strata of the alirocumab group, patients differed by baseline LDL-C, lipoprotein(a), use of intensive statin therapy, study medication adherence, and other demographic, medical history, biometric, and laboratory criteria. After propensity score matching, characteristics were similar in corresponding patients of the alirocumab and placebo groups. Treatment hazard ratio, 95% CI, and absolute risk reduction (number per 100 patient-years) for MACE were similar in those with achieved LDL-C <25 mg/dL (hazard ratio, 0.74 [95% CI, 0.62-0.89]; absolute risk reduction, 0.92) or 25 to 50 mg/dL (hazard ratio, 0.74 [95% CI, 0.64-0.87]; absolute risk reduction, 1.05). Patients with achieved LDL-C >50 mg/dL had poorer adherence and derived less benefit (hazard ratio, 0.87 [95% CI, 0.73-1.04]; absolute risk reduction, 0.62). No safety concerns were associated with a limited period of LDL-C levels <15 mg/dL. CONCLUSIONS After accounting for differences in baseline characteristics and adherence, patients treated with alirocumab who achieved LDL-C levels <25 mg/dL had a reduction in the risk of MACE that was similar to that of patients who achieved LDL-C levels of 25 to 50 mg/dL. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.
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Dietary Strawberries Improve Cardiometabolic Risks in Adults with Obesity and Elevated Serum LDL Cholesterol in a Randomized Controlled Crossover Trial.
Basu, A, Izuora, K, Betts, NM, Kinney, JW, Salazar, AM, Ebersole, JL, Scofield, RH
Nutrients. 2021;(5)
Abstract
Background and aims: Dietary berries, such as strawberries, are rich in bioactive compounds and have been shown to lower cardiometabolic risk. We examined the effects of two dietary achievable doses of strawberries on glycemic control and lipid profiles in obese adults with elevated serum LDL cholesterol (LDL-C). Methods: In this 14-week randomized controlled crossover study, participants were assigned to one of the three arms for four weeks separated by a one-week washout period: control powder, one serving (low dose: 13 g strawberry powder/day), or two-and-a -half servings (high dose: 32 g strawberry powder/day). Participants were instructed to follow their usual diet and lifestyle while refraining from consuming other berries and related products throughout the study interval. Blood samples, anthropometric measures, blood pressure, and dietary and physical activity data were collected at baseline and at the end of each four-week phase of intervention. Results: In total, 33 participants completed all three phases of the trial [(mean ± SD): Age: 53 ± 13 y; BMI: 33 ± 3.0 kg/m2). Findings revealed significant reductions in fasting insulin (p = 0.0002) and homeostatic model of assessment of insulin resistance (p = 0.0003) following the high dose strawberry phase when compared to the low dose strawberry and control phases. Glucose and conventional lipid profiles did not differ among the phases. Nuclear magnetic resonance-determined particle concentrations of total VLDL and chylomicrons, small VLDL, and total and small LDL were significantly decreased after the high dose strawberry phase, compared to control and low dose phases (all p < 0.0001). Among the biomarkers of inflammation and adipokines measured, only serum PAI-1 showed a decrease after the high dose strawberry phase (p = 0.002). Conclusions: These data suggest that consuming strawberries at two-and-a-half servings for four weeks significantly improves insulin resistance, lipid particle profiles, and serum PAI-1 in obese adults with elevated serum LDL-C.
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Supplementation with Octacosanol Affects the Level of PCSK9 and Restore Its Physiologic Relation with LDL-C in Patients on Chronic Statin Therapy.
Ciric, MZ, Ostojic, M, Baralic, I, Kotur-Stevuljevic, J, Djordjevic, BI, Markovic, S, Zivkovic, S, Stankovic, I
Nutrients. 2021;(3)
Abstract
Dietary supplementation with sugar cane derivates may modulate low-density lipoprotein cholesterol (LDL-C) and proprotein convertase subtilisin/kexin type 9 (PCSK9) levels. The purpose of this study was to determine if dietary supplement (DS), containing Octacosanol (20 mg) and vitamin K2 (45 µg), could restore the disrupted physiologic relation between LDL-C and serum PCSK9. Double-blind, randomized, placebo-controlled, single-center study including 87 patients on chronic atorvastatin therapy was conducted. Eighty-seven patients were randomized to receive DS (n = 42) or placebo (n = 45), and followed for 13 weeks. Serum PCSK9 levels, lipid parameters and their relationship were the main efficacy endpoints. The absolute levels of PCSK9 and LDL-C were not significantly different from baseline to 13 weeks. However, physiologic correlation between % change of PCSK9 and % change of LDL-C levels was normalized only in the group of patients treated with DS (r = 0.409, p = 0.012). This study shows that DS can restore statin disrupted physiologic positive correlation between PCSK9 and LDL-C. Elevated PCSK9 level is an independent risk factor so controlling its rise by statins may be important in prevention of cardiovascular events.
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A Non-Probiotic Fermented Soy Product Reduces Total and LDL Cholesterol: A Randomized Controlled Crossover Trial.
Jung, SM, Haddad, EH, Kaur, A, Sirirat, R, Kim, AY, Oda, K, Rajaram, S, Sabaté, J
Nutrients. 2021;(2)
Abstract
Traditional Asian fermented soy food products are associated with reduced cardiovascular disease risk in prospective studies, but few randomized controlled trials have been conducted in at-risk populations. The aim of this study was to investigate the effect of a commercial non-probiotic fermented soy product on blood lipids in adults with cardiovascular risk biomarkers. In a randomized, crossover, intervention study, 27 men and women (aged 29-75 y) exhibiting at least two risk factors, consumed two packets (12.5 g each) daily of a fermented powdered soy product, or an isoenergic control powder made from germinated brown rice for 12 weeks each. The consumption of the fermented soy product resulted in a significantly greater mean change from baseline (compared to the germinated rice, all p < 0.05) in total cholesterol of -0.23 mmol/L (CI: -0.40, -0.06) compared with 0.14 mmol/L (CI: -0.03, 0.31), respectively; and low density lipoprotein (LDL) cholesterol -0.18 mmol/L (CI: -0.32, -0.04) compared with 0.04 mmol/L (CI: -0.01, 0.018) respectively. This was accompanied by an increase in high density lipoprotein (HDL) cholesterol in the germinated rice group, a decrease in apolipoprotein B (ApoB) in the fermented soy group, and a between-treatment effect in apolipoprotein A1 (ApoA1); however, the ratio of the LDL:HDL and of Apo B:ApoA1 did not differ between the groups. The ratio of total cholesterol:LDL decreased in men in the fermented soy group (p < 0.001). Twenty-four-hour urine collection at the end of each treatment period resulted in an increased excretion expressed as a ratio in μmol/d between treatments of 10.93 (CI: 5.07, 23.54) for daidzein; 1.24 (CI: 1.14, 4.43) for genistein; and, 8.48 (CI: 4.28, 16.80) for glycitein, all p < 0.05. The fermented soy powder consumed by participants in this study without implementing other changes in their typical diets, decreased the total and LDL cholesterol, and may serve as a dietary strategy to manage blood lipids. The trial was registered at ClinicalTrials.gov as NCT03429920.
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Adherence at 2 years with distribution of essential medicines at no charge: The CLEAN Meds randomized clinical trial.
Persaud, N, Bedard, M, Boozary, A, Glazier, RH, Gomes, T, Hwang, SW, Juni, P, Law, MR, Mamdani, M, Manns, B, et al
PLoS medicine. 2021;(5):e1003590
Abstract
BACKGROUND Adherence to medicines is low for a variety of reasons, including the cost borne by patients. Some jurisdictions publicly fund medicines for the general population, but many jurisdictions do not, and such policies are contentious. To our knowledge, no trials studying free access to a wide range of medicines have been conducted. METHODS AND FINDINGS We randomly assigned 786 primary care patients who reported not taking medicines due to cost between June 1, 2016 and April 28, 2017 to either free distribution of essential medicines (n = 395) or to usual medicine access (n = 391). The trial was conducted in Ontario, Canada, where hospital care and physician services are publicly funded for the general population but medicines are not. The trial population was mostly female (56%), younger than 65 years (83%), white (66%), and had a low income from wages as the primary source (56%). The primary outcome was medicine adherence after 2 years. Secondary outcomes included control of diabetes, blood pressure, and low-density lipoprotein (LDL) cholesterol in patients taking relevant treatments and healthcare costs over 2 years. Adherence to all appropriate prescribed medicines was 38.7% in the free distribution group and 28.6% in the usual access group after 2 years (absolute difference 10.1%; 95% confidence interval (CI) 3.3 to 16.9, p = 0.004). There were no statistically significant differences in control of diabetes (hemoglobin A1c 0.27; 95% CI -0.25 to 0.79, p = 0.302), systolic blood pressure (-3.9; 95% CI -9.9 to 2.2, p = 0.210), or LDL cholesterol (0.26; 95% CI -0.08 to 0.60, p = 0.130) based on available data. Total healthcare costs over 2 years were lower with free distribution (difference in median CAN$1,117; 95% CI CAN$445 to CAN$1,778, p = 0.006). In the free distribution group, 51 participants experienced a serious adverse event, while 68 participants in the usual access group experienced a serious adverse event (p = 0.091). Participants were not blinded, and some outcomes depended on participant reports. CONCLUSIONS In this study, we observed that free distribution of essential medicines to patients with cost-related nonadherence substantially increased adherence, did not affect surrogate health outcomes, and reduced total healthcare costs over 2 years. TRIAL REGISTRATION ClinicalTrials.gov NCT02744963.
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A structurally optimized FXR agonist, MET409, reduced liver fat content over 12 weeks in patients with non-alcoholic steatohepatitis.
Harrison, SA, Bashir, MR, Lee, KJ, Shim-Lopez, J, Lee, J, Wagner, B, Smith, ND, Chen, HC, Lawitz, EJ
Journal of hepatology. 2021;(1):25-33
Abstract
BACKGROUND & AIMS The benefits of farnesoid X receptor (FXR) agonists in patients with non-alcoholic steatohepatitis (NASH) have been validated, although improvements in efficacy and/or tolerability remain elusive. Herein, we aimed to assess the performance of a structurally optimized FXR agonist in patients with NASH. METHODS In this 12-week, randomized, placebo-controlled study, we evaluated MET409 - a non-bile acid agonist with a unique chemical scaffold - in patients with NASH. Patients were randomized to receive either 80 mg (n = 20) or 50 mg (n = 19) of MET409, or placebo (n = 19). RESULTS At Week 12, MET409 lowered liver fat content (LFC), with mean relative reductions of 55% (80 mg) and 38% (50 mg) vs. 6% in placebo (p <0.001). MET409 achieved ≥30% relative LFC reduction in 93% (80 mg) and 75% (50 mg) of patients vs. 11% in placebo (p <0.001) and normalized LFC (≤5%) in 29% (80 mg) and 31% (50 mg) of patients vs. 0% in placebo (p <0.05). An increase in alanine aminotransferase (ALT) was observed with MET409, confounding Week 12 changes from baseline (-25% for 80 mg, 28% for 50 mg). Nonetheless, MET409 achieved ≥30% relative ALT reduction in 50% (80 mg) and 31% (50 mg) of patients vs. 17% in placebo. MET409 was associated with on-target high-density lipoprotein cholesterol decreases (mean changes of -23.4% for 80 mg and -20.3% for 50 mg vs. 2.6% in placebo) and low-density lipoprotein cholesterol (LDL-C) increases (mean changes of 23.7% for 80 mg and 6.8% for 50 mg vs. -1.5% in placebo). Pruritus (mild-moderate) occurred in 16% (50 mg) and 40% (80 mg) of MET409-treated patients. CONCLUSION MET409 lowered LFC over 12 weeks in patients with NASH and delivered a differentiated pruritus and LDL-C profile at 50 mg, providing the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced through structural optimization. LAY SUMMARY Activation of the farnesoid X receptor (FXR) is a clinically validated approach for treating non-alcoholic steatohepatitis (NASH), although side effects such as itching or increases in low-density lipoprotein cholesterol are frequently dose-limiting. MET409, an FXR agonist with a unique chemical structure, led to significant liver fat reduction and delivered a favorable side effect profile after 12 weeks of treatment in patients with NASH. These results provide the first clinical evidence that the risk-benefit profile of FXR agonists can be enhanced.
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Effect of inclisiran, the small-interfering RNA against proprotein convertase subtilisin/kexin type 9, on platelets, immune cells, and immunological biomarkers: a pre-specified analysis from ORION-1.
Landmesser, U, Haghikia, A, Leiter, LA, Wright, RS, Kallend, D, Wijngaard, P, Stoekenbroek, R, Kastelein, JJ, Ray, KK
Cardiovascular research. 2021;(1):284-291
Abstract
AIMS: Small-interfering RNA (siRNA)-based targeting of proprotein convertase subtilisin/kexin type 9 (PCSK9) represents a novel therapeutic approach that may provide a convenient, infrequent, and safe dosing schedule to robustly lower low-density lipoprotein cholesterol (LDL-C). Given the long duration of action, however, establishing safety in particular with respect to immunogenicity is of paramount importance. In earlier clinical studies of other RNA-targeted treatment approaches (antisense oligonucleotide therapy) immunological and haematological adverse effects, in particular thrombocytopenia and pro-inflammatory effects, have been reported. Here, we present the pre-specified safety analysis from ORION-1 evaluating platelets, immune cells, immunological markers, antidrug antibodies, and clinical immunogenicity adverse events (AEs) under PCSK9 siRNA treatment with inclisiran. METHODS AND RESULTS The pre-specified safety analysis from ORION-1 was performed in six different inclisiran dosing regimens in patients at high risk of cardiovascular disease with elevated LDL-C levels. Patients received either a single dose (SD: 200 mg, n = 60; 300 mg, n = 62 or 500 mg, n = 66) or double-dose starting regimen (DD: 100 mg, n = 62; 200 mg, n = 63; or 300 mg, n = 61 on days 1 and 90) of inclisiran or placebo (SD: n = 65; DD: n = 62). The effects of inclisiran on haematological parameters including platelet counts, lymphocytes, and monocytes as well as on the immune markers interleukin 6 (IL-6) and tumour necrosis factor-α (TNF-α) were examined after 180 days. Immunogenicity was further evaluated by analysis of anti-drug-antibodies (ADAs) towards inclisiran in 6068 study samples and by careful analysis of immunogenicity AEs as part of the pharmacovigilance strategy. At day 180, no significant alterations of platelet counts were observed in any of the dosing groups (change from baseline, SD: 200 mg: 0.8%; 300 mg: -0.5%; 500 mg: -1.8%; DD: 100 mg: 1.3%; 200 mg: -0.5%; 300 mg: 1.0%; no significant difference for any group as compared with placebo). No significant effects on other immune cells, including leucocytes, monocytes, or neutrophils were detected. Notably, no significant increase of inflammatory biomarkers (IL-6 or TNF-α) with either the SD or DD regimen became evident. There was no evidence for immunogenicity based on ADA level analysis and careful review of clinical immunogenicity AEs in none of the treatment regimens. CONCLUSION In this pre-specified safety analysis of ORION-1 for the siRNA therapeutic inclisiran, no adverse effects on measures of inflammation or immune activation nor adverse effects on platelets or clinical immunogenicity AEs were observed over at least 6-month treatment. These safety findings in the largest analysis of an RNAi study in humans to date provide strong reassurance about the safety of inclisiran and the potential of cardiovascular RNA-targeted therapies.
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Nurse-led, telephone-based follow-up after acute coronary syndrome yields improved risk factors after 36 months: the randomized controlled NAILED-ACS trial.
Henriksson, R, Huber, D, Mooe, T
Scientific reports. 2021;(1):17693
Abstract
We investigated whether a nurse-led, telephone-based follow-up including medical titration was superior to usual care in improving blood pressure (BP) and low-density lipoprotein cholesterol (LDL-C) values 36 months after acute coronary syndrome (ACS). We screened all patients admitted with ACS at Östersund hospital, Sweden, between January 1, 2010, and December 31, 2014, for inclusion based on ability to participate in a telephone-based follow-up. Participants were randomly allocated to usual care or an intervention group that received counselling and medical titration to target BP < 140/< 90 mmHg and LDL-C < 2.5/< 1.8 mmol/L. The primary outcome was LDL-C at 36 months. Of 962 patients, 797 (83%) were available for analysis after 36 months. Compared to controls, the intervention group had a mean systolic BP (SBP) 4.1 mmHg lower (95% confidence interval [CI] 1.9-6.5), mean diastolic BP (DBP) 2.9 mmHg lower (95% CI 1.5-4.5), and mean LDL-C 0.28 mmol/L lower (95% CI 0.135-0.42). All P < 0.001. A significantly greater proportion of patients reached treatment targets with the intervention. After 36 months of follow-up, compared to usual care, the nurse-led, telephone-based intervention led to significantly lower SBP, DBP, and LDL-C and to a larger proportion of patients meeting target values.Trial registration: ISRCTN registry. Trial number ISRCTN96595458. Retrospectively registered.
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Randomized parallel-group pilot trial (Best foods for your heart) comparing the effects of a Mediterranean Portfolio diet with a low saturated fat diet on HIV dyslipidemia.
Stradling, C, Thomas, GN, Hemming, K, Taylor, S, Taheri, S
Clinical nutrition (Edinburgh, Scotland). 2021;(3):860-869
Abstract
BACKGROUND & AIMS Mediterranean diets reduce the risk of cardiovascular disease (CVD). However, the effect is unknown in people living with HIV, who have an increased risk potentially due to the additional burdens of infection, inflammation and antiretroviral treatment (ART). We examined the feasibility of a 6-month dietary intervention in adults with HIV dyslipidemia using a sample size adequate to detect differences in LDL-cholesterol. METHODS Sixty adults with stable HIV infection on ART and LDL-cholesterol >3 mmol/l were recruited. Participants were randomized (1:1) to receive dietary advice to reduce saturated fat intake to <10% of energy intake (Diet1), or supported to adopt the Mediterranean Portfolio Diet (Diet2) with additional cholesterol-lowering foods (nuts, stanols, soya, oats, beans) for 6 months. Recruitment, retention and intervention fidelity were monitored. Measurements were conducted at baseline, 6 and 12 months. A secondary analysis examined between group differences in CVD risk factors at month 6 adjusted for baseline values and potential confounders. RESULTS Rates of recruitment, participation and attrition were 35%, 91%, and 12% respectively. Reported dietary adherence was 68% to Mediterranean foods and 59% to Portfolio components. At 6 months Diet2 participants (n = 29) had a significantly lower LDL-cholesterol (mean difference adjusted for baseline -0.4 mmol/l, 95%CI -0.7 to -0.1, P = 0.01), and systolic blood pressure (-7 mmHg, 95%CI -2 to -12, P = 0.008) compared to those in Diet1 (n = 31). These effects were not sustained at 1 year (LDL-cholesterol -0.05 mmol/l, 95%CI -0.33 to 0.23, P = 0.7; systolic blood pressure -3.5 mmHg, 95%CI -9.4 to 2.5, P = 0.2). CONCLUSION We showed the feasibility of adopting a Mediterranean Portfolio diet in people living with HIV. Our findings suggest this intervention might equate to short term improvements in diet quality, blood pressure, and LDL-cholesterol. Further definitive evaluations are required to determine if this is a viable strategy to facilitate cardiovascular risk reduction. CLINICAL TRIAL REGISTRY ISRCTN32090191 Best Foods For your heart trial.