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Efficacy of high-dose atorvastatin or rosuvastatin loading in patients with acute coronary syndrome undergoing percutaneous coronary intervention: a meta-analysis of randomized controlled trials with GRADE qualification of available evidence.
Borovac, JA, Leth-Olsen, M, Kumric, M, D'Amario, D, Schwarz, K, Glavas, D, Bozic, J
European journal of clinical pharmacology. 2022;(1):111-126
Abstract
PURPOSE We aimed to summarize current evidence regarding the impact of a high-dose statin loading before percutaneous coronary intervention (PCI) on short-term outcomes in patients presenting with the acute coronary syndrome (ACS). METHODS This meta-analysis was based on a search of the MEDLINE, Cochrane Central Register of Controlled Trials, Ovid Journals, and SCOPUS for randomized controlled trials that compared high-dose atorvastatin or rosuvastatin with no or low-dose statin administered before planned PCI in statin-naive patients with ACS. The primary endpoints were major adverse cardiovascular and cerebrovascular events (MACCE), myocardial infarction (MI), and all-cause mortality at 30 days. Prespecified subanalyses were performed with respect to statin and ACS type. RESULTS A total of eleven trials enrolling 6291 patients were included, of which 75.4% received PCI. High-dose statin loading was associated with an overall 43% relative risk (RR) reduction in MACCE at 30 days (RR 0.57, 95% CI 0.41-0.77) in whole ACS population. This effect was primarily driven by the 39% reduction in the occurrence of MI (RR 0.61, 95% CI 0.46-0.80). No significant effect on all-cause mortality reduction was observed (RR 0.92, 95% CI 0.67-1.26). In the setting of ST-elevation myocardial infarction (STEMI), atorvastatin loading was associated with a 33% reduction in MACCE (RR 0.67, 95% CI 0.48-0.94), while in non-ST-elevation myocardial infarction ACS (NSTE-ACS), rosuvastatin loading was associated with 52% reduction in MACCE at 30 days (RR 0.48, 95% CI 0.34-0.66). The level of evidence as qualified with GRADE was low to high, depending on the outcome. CONCLUSION A high-dose loading of statins before PCI in patients with ACS reduces MACCE and reduces the risk of MI with no impact on mortality at 30 days. Atorvastatin reduces MACCE in STEMI while rosuvastatin reduces MACCE in NSTE-ACS at 30 days.
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Antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia: A systemic review and meta-analysis of randomized studies.
Lee, S, Yang, S, Chang, MJ
PloS one. 2021;(11):e0260391
Abstract
Some studies have suggested the antihypertensive effects of statins, a class of lipid-lowering agents, particularly in patients with hypertension. However, the evidence for the role of statins in blood pressure (BP) lowering is controversial, and no meta-analysis of rosuvastatin therapy has been conducted to assess its BP-lowering effects. Therefore, the aim of this meta-analysis of randomized controlled trials (RCTs) was to investigate the effects of rosuvastatin on systolic blood pressure (SBP) and diastolic blood pressure (DBP) in patients with hypertension. We systematically searched the electronic databases MEDLINE, EMBASE, and Cochrane Library to identify RCTs in which patients were assigned to groups of rosuvastatin plus antihypertensive agents vs. antihypertensive agents. The three authors independently selected the studies, extracted data, and assessed methodological quality. We included five RCTs in this meta-analysis with 288 patients treated with rosuvastatin and 219 patients without rosuvastatin. The mean DBP in the rosuvastatin group was significantly lower than that in the non-rosuvastatin group by -2.12 mmHg (95% confidence interval (CI) -3.72 to -0.52; Pfixed-effects model = 0.009; I2 = 0%, Pheterogeneity = 0.97). Rosuvastatin treatment also lowered the mean SBP compared with the non-rosuvastatin treatment by -2.27 mmHg, but not significantly (95% CI - 4.75 to 0.25; Pfixed-effects model = 0.08; I2 = 0%, Pheterogeneity = 0.82). In this study, we reviewed the antihypertensive effects of rosuvastatin in patients with hypertension and dyslipidemia. We demonstrated a modest significant reduction of DBP and a trend toward a lowered SBP in patients with hypertension with rosuvastatin therapy. Rosuvastatin could be beneficial to control hypertension and, consequently, contribute toward reducing the risk of cardiovascular events in patients with hypertension and dyslipidemia.
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Impact of Lowering Low-Density Lipoprotein Cholesterol with Contemporary Lipid-Lowering Medicines on Cognitive Function: A Systematic Review and Meta-Analysis.
Ying, H, Wang, J, Shen, Z, Wang, M, Zhou, B
Cardiovascular drugs and therapy. 2021;(1):153-166
Abstract
PURPOSE To evaluate the potential association between the lowering of low-density lipoprotein cholesterol (LDL-C) with contemporary lipid-lowering medicines and cognitive function. METHODS Randomized controlled trials (RCTs) in databases including PubMed, Embase, and the Web of Science and all databases in the Cochrane Library and ClinicalTrials.gov were collected from inception to January 1, 2020. The cognitive function of patients receiving proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, statins and ezetimibe was evaluated using meta-analysis. RESULTS A total of 2910 studies were obtained from databases and other sources. Thirty-three studies were selected by screening, including 11 studies on alirocumab, 9 studies on evolocumab, 11 studies on statins and 2 studies on ezetimibe. In our study, a total of 128,691 patients with no cognitive impairment were divided into an intervention group (66,330 patients) and a control group (62,361 patients). The data were subjected to a random-effects model or a fixed-effects model for meta-analysis. The contemporary lipid-lowering medicines significantly reduced LDL-C in terms of both percentage (WMD: -45.06%, 95% CI -50.12% to -40.00%, P < 0.001) and absolute value (WMD: -64.01 mg/dL, 95% CI -72.25 to -55.78, P < 0.001). Compared with the control group, patients receiving treatment with contemporary lipid-lowering medicines did not show a significant difference in the rate of neurocognitive disorder (RR: 1.02, 95% CI 0.90 to 1.16, I2 = 0.0%, p = 0.696). Subgroup analysis was performed according to the intervention and LDL-C stratification. The result of this subgroup analysis was consistent with the main findings. Regarding global cognitive performance, no difference in major cognition was found among the pooled data (SMD: 0.02, 95% CI -0.01 to 0.04, P = 0.002), except for psychomotor speed (SMD: 0.09, 95% CI 0.02 to 0.16, P = 0.0024). CONCLUSIONS Contemporary lipid-lowering medicines were not associated with cognitive impairment in RCTs. A low LDL-C level did not influence the incidence of cognitive disorder or global cognitive performance.
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Cholesteryl ester transfer protein (CETP) as a drug target for cardiovascular disease.
Schmidt, AF, Hunt, NB, Gordillo-Marañón, M, Charoen, P, Drenos, F, Kivimaki, M, Lawlor, DA, Giambartolomei, C, Papacosta, O, Chaturvedi, N, et al
Nature communications. 2021;(1):5640
Abstract
Development of cholesteryl ester transfer protein (CETP) inhibitors for coronary heart disease (CHD) has yet to deliver licensed medicines. To distinguish compound from drug target failure, we compared evidence from clinical trials and drug target Mendelian randomization of CETP protein concentration, comparing this to Mendelian randomization of proprotein convertase subtilisin/kexin type 9 (PCSK9). We show that previous failures of CETP inhibitors are likely compound related, as illustrated by significant degrees of between-compound heterogeneity in effects on lipids, blood pressure, and clinical outcomes observed in trials. On-target CETP inhibition, assessed through Mendelian randomization, is expected to reduce the risk of CHD, heart failure, diabetes, and chronic kidney disease, while increasing the risk of age-related macular degeneration. In contrast, lower PCSK9 concentration is anticipated to decrease the risk of CHD, heart failure, atrial fibrillation, chronic kidney disease, multiple sclerosis, and stroke, while potentially increasing the risk of Alzheimer's disease and asthma. Due to distinct effects on lipoprotein metabolite profiles, joint inhibition of CETP and PCSK9 may provide added benefit. In conclusion, we provide genetic evidence that CETP is an effective target for CHD prevention but with a potential on-target adverse effect on age-related macular degeneration.
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Meta-analysis of the Relation of Body Mass Index to Cardiovascular Outcomes in Patients Receiving Intensive Low-Density Lipoprotein Cholesterol Lowering Therapy.
Khan, SU, Khan, MU, Riaz, H, Raggi, P, Valavoor, S, Khan, MZ, Kołodziejczak, M, Khan, MS, Krupica, T, Alkhouli, M, et al
The American journal of cardiology. 2020;(5):727-734
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Abstract
The impact of body mass index (BMI) on cardiovascular outcomes in patients receiving intensive low-density lipoprotein cholesterol (LDL-C) lowering therapy is uncertain. We performed meta-analysis of 29 randomized controlled trials using PubMed, Embase, and CENTRAL through April 2019. Therapies were grouped as more intensive LDL-C lowering therapy (statins, ezetimibe + statin or PCSK9 inhibitors) and less intensive LDL-C lowering therapy (less potent active control or placebo). Random effects meta-regressions and meta-analyses were performed to evaluate association of BMI with cardiovascular endpoints. In 265,766 patients, for every 1 kg/m2 increase in BMI, more intensive therapy compared with less intensive therapy was associated with hazard ratio (HR) of 1.07 for cardiovascular mortality (95% confidence interval 1.02 to 1.13); HR of 1.03 for all-cause mortality (0.99 to 1.06) HR of 1.06 for myocardial infarction (1.02 to 1.09), HR of 1.08 (1.03 to 1.12) for revascularization and HR of 1.04 for MACE (1.01 to 1.07). Meta-analysis showed that patients with BMI <25 kg/m2 had the highest risk reduction in mortality and cardiovascular outcomes compared with patients with BMI ≥30 kg/m2 (p-interaction ≤0.05). In conclusion, patients with normal BMI treated with intensive LDL-C lowering regimens may derive a larger clinical benefit compared with patients with larger BMI. The results could be due to the higher mortality rate of obese patients that may artificially lower the efficacy of therapy, or due to a true therapeutic limitation in these patients.
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Lipid-Lowering Efficacy of Ezetimibe in Patients with Atherosclerotic Cardiovascular Disease: A Systematic Review and Meta-Analyses.
Shaya, FT, Sing, K, Milam, R, Husain, F, Del Aguila, MA, Patel, MY
American journal of cardiovascular drugs : drugs, devices, and other interventions. 2020;(3):239-248
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INTRODUCTION Patients with atherosclerotic cardiovascular disease (ASCVD), especially those with recent (< 1 year) acute coronary syndrome (ACS), are at high risk for recurrent cardiovascular events. This risk can be reduced by lowering low-density lipoprotein cholesterol (LDL-C) levels. A comprehensive meta-analysis on the LDL-C-lowering efficacy of ezetimibe is lacking. This study attempts to address this gap. METHODS A systematic literature review of randomized controlled trials evaluating the LDL-C-lowering efficacy of ezetimibe in the ASCVD population was conducted. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials were searched for publications from database inception to August 2018 and for conference abstracts from 2015 to August 2018. Meta-analyses were conducted to evaluate the LDL-C-lowering efficacy of ezetimibe in the ASCVD population and the recent ACS subgroup. RESULTS In total, 12 studies were eligible for the meta-analyses. Treatment with combination ezetimibe plus statin therapy showed greater absolute LDL-C reduction than statin monotherapy (mean difference - 21.86 mg/dL; 95% confidence interval [CI] - 26.56 to - 17.17; p < 0.0001) after 6 months of treatment (or at a timepoint closest to 6 months). Similarly, in patients with recent ACS, combination ezetimibe plus statin therapy was favorable compared with statin monotherapy (mean treatment difference - 19.19 mg/dL; 95% CI - 25.22 to - 13.16; p < 0.0001). CONCLUSIONS Ezetimibe, when added to statin therapy, provided a modest additional reduction in LDL-C compared with statin monotherapy. However, this may not be sufficient for some patients with ASCVD who have especially high LDL-C levels despite optimal statin therapy.
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Residual inflammatory risk after contemporary lipid lowering therapy.
Riaz, H, Khan, SU, Lateef, N, Talluri, S, Khan, MS, Desai, MY
European heart journal. Quality of care & clinical outcomes. 2020;(2):105-111
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BACKGROUND Recently, there has been an increasing interest in targeting inflammation to reduce major adverse cardiovascular events (MACE) in patients with cardiovascular risk. Statins, PCSK9 inhibitors, and ezetimibe have been shown to reduce MACE owing to reduction in low-density lipoproteins cholesterol (LDL-c). Herein, we investigate whether the intensity of these agents is associated with (i) discernible reduction in inflammation measured by the levels of high-sensitivity C-reactive protein (hsCRP); (ii) reduction in MACE; (iii) if there is an association between the baseline hsCRP and MACE. METHODS AND RESULTS Electronic databases were searched for randomized controlled trials (RCTs) that compared statins, ezetimibe, PCSK9 inhibitors with placebos/active controls and reported MACEs and hsCRP (mg/L). Studies were stratified based on baseline hsCRP (<2, 2-3, >3) with subgroup analysis conducted across each stratum. Fourteen RCTs including 133 109 patients randomized into more intensive therapy (MIT) and less intensive therapy were selected. Meta-analysis did not demonstrate any significant differences between use of MIT and hsCRP levels (mean difference, -0.02; CI, -0.06, 0.02; P = 0.31). The MIT significantly reduced the risk of MACE (RR, 0.82; CI, 0.75, 0.91; P < 0.001). The relative risk and absolute risk remained consistent across the strata. However, there was a 0.5% statistically significant absolute risk reduction in all-cause mortality in patients with higher hsCRP (RD, -0.005; CI, -0.009, -0.001; P = 0.01). CONCLUSION Overall, LDL-c lowering therapies reduce relative risk of MACEs particularly in patients with higher baseline hsCRP. However, there appears to be a residual inflammatory risk despite the use of contemporary lipid lowering agents.
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Efficacy and safety of bempedoic acid alone or combining with other lipid-lowering therapies in hypercholesterolemic patients: a meta-analysis of randomized controlled trials.
Zhao, X, Ma, X, Luo, X, Shi, Z, Deng, Z, Jin, Y, Xiao, Z, Tan, L, Liu, P, Jiang, S, et al
BMC pharmacology & toxicology. 2020;(1):86
Abstract
BACKGROUND Bempedoic acid is a new drug that reduces cholesterol synthesis via inhibiting ATP citrate lyase. It remains unclear whether the combination of bempedoic acid and other lipid-lowering drugs is better than these drugs alone. This study systematically reviewed the efficacy and safety of bempedoic acid monotherapy or combination togethers in hypercholesterolemic patients. METHODS Randomized controlled trials were searched across Medline, Embase, Cochrane library, web of science, etc. The net change scores [least squares mean (LSM) percentage change] in LDL-C level were meta-analyzed using weighted mean difference. The reductions in other lipids including total cholesterol (TC), non-high-density lipoprotein cholesterol (non-HDL-C) and apolipoprotein (ApoB) and high sensitivity C reactive protein (hsCRP) were also assessed. Odds ratio (OR) of the incidence of adverse events (AEs) were calculated to evaluate the safety of bempedoic acid. RESULTS A total of 13 trials (4858 participates) were included. Pooled data showed that the combination togethers resulted in greater reductions in LDL-C level than monotherapies (bempedoic acid + statin vs. statin: LSM difference (%), - 18.37, 95% CI, - 20.16 to - 16.57, I2 = 0; bempedoic acid + ezetimibe vs. ezetimibe: LSM difference (%), - 18.89, 95% CI, - 29.66 to - 8.13, I2 = 87%). But the difference in efficacy between bempedoic acid and ezetimibe was not obvious. Meta-regression analysis showed the treatment duration was a source of heterogeneity (adj R2 = 16.92, 95% CI, 0.04 to 0.72). Furthermore, the background therapy of statin before screening decreased the efficacy of bempedoic acid. In addition, bempedoic acid also resulted in a significant reduction in TC, non-HDL-C, ApoB and hsCRP level. The OR of muscle-related AEs by the combination of bempedoic acid and statin was 1.29 (95% CI, 1.00 to 1.67, I2 = 0) when compared with statin alone. CONCLUSION This study showed the efficacy of combination togethers were similar but stronger than these drugs alone. Of note, a trend of high risk of muscle-related AEs by the combination of bempedoic acid and statin was observed, though it is not statistically significant, such risk is needed to be confirmed by more trials, because it is important for us to determine which is the better combinative administration for statin-intolerant patients.
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PCSK9 inhibitors and cardiovascular outcomes.
Steffens, D, Bramlage, P, Scheeff, C, Kasner, M, Hassanein, A, Friebel, J, Rauch-Kröhnert, U
Expert opinion on biological therapy. 2020;(1):35-47
Abstract
Introduction: Dyslipidemia, particularly elevated low-density lipoprotein cholesterol (LDL-C), is a key risk factor for atherosclerotic cardiovascular disease (ASCVD), and lipid-lowering drugs are beneficial for the primary and secondary prevention of cardiovascular (CV) disease. While statins are clear first-line drugs, new drug developments such as proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to improve cardiovascular outcomes when added to statins. Evolocumab reduced the risk of cardiovascular events in patients with ASCVD when added to maximally tolerated statin therapy (± ezetimibe), and recent data from the ODYSSEY OUTCOMES trial indicate that alirocumab added to maximally tolerated statin therapy (± other lipid-lowering drugs) reduces the risk of cardiovascular events in patients with a recent acute coronary syndrome. In this article the authors review the available data on the effect of PCSK9 inhibitors on cardiovascular outcomes.Areas covered: This article reviews the available data on the effect of PCSK9 inhibitors on CV outcomes. Relevant papers were identified from a search of PubMed/Medline and the Cochrane Central Register of Controlled Trials (CENTRAL).Expert opinion: The authors conclude that PCSK9 inhibitors provide substantial and durable reductions in LDL-C levels and improve cardiovascular outcomes.
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Diet and Cardiovascular Disease Risk Among Individuals with Familial Hypercholesterolemia: Systematic Review and Meta-Analysis.
Barkas, F, Nomikos, T, Liberopoulos, E, Panagiotakos, D
Nutrients. 2020;(8)
Abstract
BACKGROUND Although a cholesterol-lowering diet and the addition of plant sterols and stanols are suggested for the lipid management of children and adults with familial hypercholesterolemia, there is limited evidence evaluating such interventions in this population. OBJECTIVES To investigate the impact of cholesterol-lowering diet and other dietary interventions on the incidence or mortality of cardiovascular disease and lipid profile of patients with familial hypercholesterolemia. SEARCH METHODS Relevant trials were identified by searching US National Library of Medicine National Institutes of Health Metabolism Trials Register and clinicaltrials.gov.gr using the following terms: diet, dietary, plant sterols, stanols, omega-3 fatty acids, fiber and familial hypercholesterolemia. SELECTION CRITERIA Randomized controlled trials evaluating the effect of cholesterol-lowering diet or other dietary interventions in children and adults with familial hypercholesterolemia were included. DATA COLLECTION AND ANALYSIS Two authors independently assessed the eligibility of the included trials and their bias risk and extracted the data which was independently verified by other colleagues. RESULTS A total of 17 trials were finally included, with a total of 376 participants across 8 comparison groups. The included trials had either a low or unclear bias risk for most of the assessed risk parameters. Cardiovascular incidence or mortality were not evaluated in any of the included trials. Among the planned comparisons regarding patients' lipidemic profile, a significant difference was noticed for the following comparisons and outcomes: omega-3 fatty acids reduced triglycerides (mean difference (MD): -0.27 mmol/L, 95% confidence interval (CI): -0.47 to -0.07, p < 0.01) when compared with placebo. A non-significant trend towards a reduction in subjects' total cholesterol (MD: -0.34, 95% CI: -0.68 to 0, mmol/L, p = 0.05) and low-density lipoprotein cholesterol (MD: -0.31, 95% CI: -0.61 to 0, mmol/L, p = 0.05) was noticed. In comparison with cholesterol-lowering diet, the additional consumption of plant stanols decreased total cholesterol (MD: -0.62 mmol/L, 95% CI: -1.13 to -0.11, p = 0.02) and low-density lipoprotein cholesterol (MD: -0.58 mmol/L, 95% CI: -1.08 to -0.09, p = 0.02). The same was by plant sterols (MD: -0.46 mmol/L, 95% CI: -0.76 to -0.17, p < 0.01 for cholesterol and MD: -0.45 mmol/L, 95% CI: -0.74 to -0.16, p < 0.01 for low-density lipoprotein cholesterol). No heterogeneity was noticed among the studies included in these analyses. CONCLUSIONS Available trials confirm that the addition of plant sterols or stanols has a cholesterol-lowering effect on such individuals. On the other hand, supplementation with omega-3 fatty acids effectively reduces triglycerides and might have a role in lowering the cholesterol of patients with familial hypercholesterolemia. Additional studies are needed to investigate the efficacy of cholesterol-lowering diet or the addition of soya protein and dietary fibers to a cholesterol-lowering diet in patients with familial hypercholesterolemia.