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Derivation and Application of a Tool to Estimate Benefits From Multiple Therapies That Reduce Recurrent Stroke Risk.
Richards, A, Jackson, NJ, Cheng, EM, Bryg, RJ, Brown, A, Towfighi, A, Sanossian, N, Barry, F, Li, N, Vickrey, BG
Stroke. 2020;(5):1563-1569
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Background and Purpose- Lowering blood pressure and cholesterol, antiplatelet/antithrombotic use, and smoking cessation reduce risk of recurrent stroke. However, gaps in risk factor control among stroke survivors warrant development and evaluation of alternative care delivery models that aim to simultaneously improve multiple risk factors. Randomized trials of care delivery models are rarely of sufficient duration or size to be powered for low-frequency outcomes such as observed recurrent stroke. This creates a need for tools to estimate how changes across multiple stroke risk factors reduce risk of recurrent stroke. Methods- We reviewed existing evidence of the efficacy of interventions addressing blood pressure reduction, cholesterol lowering, antiplatelet/antithrombotic use, and smoking cessation and extracted relative risks for each intervention. From this, we developed a tool to estimate reductions in recurrent stroke risk, using bootstrapping and simulation methods. We also calculated a modified Global Outcome Score representing the proportion of potential benefit (relative risk reduction) achieved if all 4 individual risk factors were optimally controlled. We applied the tool to estimate stroke risk reduction among 275 participants with complete 12-month follow-up data from a recently published randomized trial of a healthcare delivery model that targeted multiple stroke risk factors. Results- The recurrent stroke risk tool was feasible to apply, yielding an estimated reduction in the relative risk of ischemic stroke of 0.36 in both the experimental and usual care trial arms. Global Outcome Score results suggest that participants in both arms likely averted, on average, 45% of recurrent stroke events that could possibly have been prevented through maximal implementation of interventions for all 4 individual risk factors. Conclusions- A stroke risk reduction tool facilitates estimation of the combined impact on vascular risk of improvements in multiple stroke risk factors and provides a summary outcome for studies testing alternative care models to prevent recurrent stroke. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT00861081.
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Concomitant Use of Rosuvastatin and Eicosapentaenoic Acid Significantly Prevents Native Coronary Atherosclerotic Progression in Patients With In-Stent Neoatherosclerosis.
Sugizaki, Y, Otake, H, Kuroda, K, Kawamori, H, Toba, T, Nagasawa, A, Takeshige, R, Nakano, S, Matsuoka, Y, Tanimura, K, et al
Circulation journal : official journal of the Japanese Circulation Society. 2020;(10):1826-1836
Abstract
BACKGROUND In-stent neoatherosclerosis (NA) is a risk for future cardiovascular events through atherosclerotic progression in non-stented lesions. Using optical coherence tomography, this study assessed the efficacy of intensive therapy with 10 mg/day rosuvastatin plus 1,800 mg/day eicosapentaenoic acid (EPA) vs. standard 2.5 mg/day rosuvastatin therapy on native coronary plaques in patients with NA.Methods and Results:This was a subgroup analysis of the randomized LINK-IT trial, which was designed to compare changes in the lipid index in NA between intensive and standard therapy for 12 months. In all, 42 patients with native coronary plaques and NA were assessed. Compared with standard therapy, intensive therapy resulted in greater decreases in serum low-density lipoprotein cholesterol concentrations and greater increases in serum 18-hydroxyeicosapentaenoic acid concentrations, with significantly greater decreases in the lipid index and macrophage grade in both NA (-24 vs. 217 [P<0.001] and -15 vs. 24 [P<0.001], respectively) and native coronary plaques (-112 vs. 29 [P<0.001] and -17 vs. 1 [P<0.001], respectively) following intensive therapy. Although there was a greater increase in the macrophage grade in NA than in native coronary plaques in the standard therapy group, in the intensive therapy group there were comparable reductions in macrophage grade between NA and native coronary plaques. CONCLUSIONS Compared with standard therapy, intensive therapy prevented atherosclerotic progression more effectively in native coronary plaques in patients with NA.
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Patient characteristics, treatment patterns, and adherence to lipid-lowering therapies following an acute coronary syndrome.
Bruckert, E, Desamericq, G, Khachatryan, A, Ngo, P, Gusto, G, Sorio-Vilela, F
Reviews in cardiovascular medicine. 2020;(4):643-650
Abstract
Despite dyslipidaemia management guidelines, many patients do not reach low-density lipoprotein cholesterol targets due to insufficiently intensive regimens or lack of adherence to their medication. This was a retrospective cohort study on the Pharmacoepidemiologic General Research eXtension (PGRx)-acute coronary syndrome (ACS) registry. Patients included were ≥ 18 years old who suffered an ACS between 2013 and 2016, and treated with lipid-lowering therapy (LLT) at hospital discharge or within 92 days. Patients were followed up to 12 months' post index ACS, a new cardiovascular event, loss to follow-up or death. Treatment intensity (high, moderate and low intensity statins ± ezetimibe) and adherence (proportion of days covered > 80%) are described. A total of 2,695 patients were included; mean age [SD] was 63.1 [12.8] years, and 77% were men. High, moderate and low intensity statins were started in 56% (1,520), 36% (971), and 3% (86) of patients, respectively. A further 2% (46) were on statin/ezetimibe combination, 2% (42) on other LLT and 1% (30) on ezetimibe alone. At follow-up, around 70% of patients were adherent to LLT, with those on moderate intensity treatments showing better adherence (76%) than those on low (63%) or high (67%) intensity treatments. Despite guideline recommendations, many patients following an ACS are not treated with high intensity statins, and adherence remains far from optimal. Effort should be made to increase the proportion of patients treated with high intensity statins following an ACS and to further improve treatment adherence.
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Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.
Marston, NA, Kamanu, FK, Nordio, F, Gurmu, Y, Roselli, C, Sever, PS, Pedersen, TR, Keech, AC, Wang, H, Lira Pineda, A, et al
Circulation. 2020;(8):616-623
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BACKGROUND The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. METHODS We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27-single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. RESULTS After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (Ptrend=0.005) and major coronary events (Ptrend<0.0001). Individuals with intermediate and high genetic risk scores had 1.23- and 1.65-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio [HR], 1.02; absolute risk reduction [ARR], -0.2%, P=0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75-0.998], P=0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55-0.86], P=0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk (Ptrend for HR=0.017, ARR Ptrend=0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. CONCLUSION Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.
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The Role of Nutraceuticals in the Optimization of Lipid-Lowering Therapy in High-Risk Patients with Dyslipidaemia.
Penson, PE, Banach, M
Current atherosclerosis reports. 2020;(11):67
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PURPOSE OF REVIEW We aimed to summarize recent guidelines, position papers, and high-quality clinical research relating the use of nutraceuticals in the management of individuals at high risk of atherosclerotic cardiovascular disease. RECENT FINDINGS It is essential that individuals at high risk of cardiovascular disease receive guideline-directed evidence-based therapies to reduce their risk of morbidity and mortality from cardiovascular events. Compared with conventional therapeutics, nutraceuticals have undergone relatively little investigation in randomized controlled trials. Thus, recommendations for nutraceuticals in international guidelines are rare, and nutraceuticals should not be used preferentially in place of statins. Nevertheless, recent position papers from the International Lipid Expert Panel and clinical evidence from studies of triglyceride reduction by polyunsaturated fatty acid administration demonstrate that nutraceuticals do have an important role in optimizing therapy in individuals at high risk of cardiovascular disease. Roles for nutraceuticals include as follows: (1) managing residual risk associated with lipids other than low-density lipoprotein cholesterol (LDL-C); (2) managing non-lipid-mediated residual risk; (3) optimizing LDL-C treatment in statin intolerance; (4) optimizing LCL-C treatment when add-on therapies for statins are not available; (5) as adjuncts to lifestyle for individuals at high lifetime risk of atherosclerotic cardiovascular disease (ASCVD). The strength of evidence for each of these applications is variable. In addition to guideline-directed therapeutics, nutraceuticals may have roles in optimizing preventative therapy and targeting residual risk in individuals at high risk of ASCVD. Application of Good Manufacturing Practice and randomized controlled trials when producing and evaluating nutraceuticals will expand the armoury of evidence-based agents for the prevention of ASCVD.
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PCSK9 inhibition with alirocumab in pediatric patients with heterozygous familial hypercholesterolemia: The ODYSSEY KIDS study.
Daniels, S, Caprio, S, Chaudhari, U, Manvelian, G, Baccara-Dinet, MT, Brunet, A, Scemama, M, Loizeau, V, Bruckert, E
Journal of clinical lipidology. 2020;(3):322-330.e5
Abstract
BACKGROUND Heterozygous familial hypercholesterolemia (HeFH) is a genetic disorder characterized by elevated levels of low-density lipoprotein cholesterol (LDL-C). OBJECTIVE This phase 2 dose-finding study (NCT02890992) evaluated the efficacy, safety, and dose selection of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab in pediatric HeFH patients. METHODS HeFH patients (n = 42) who were aged 8-17 years, had body weight (BW) ≥25 kg, and had LDL-C ≥130 mg/dL despite optimal statin/other lipid-modifying therapies were enrolled in 4 cohorts according to BW: cohort #1: 30 mg (<50 kg) or 50 mg (≥50 kg) every 2 weeks (Q2W), #2: 40 mg (<50 kg) or 75 mg (≥50 kg) Q2W, #3: 75 mg (<50 kg) or 150 mg (≥50 kg) every 4 weeks (Q4W), #4: 150 mg (<50 kg) or 300 mg (≥50 kg) Q4W. Primary endpoint was LDL-C % change from baseline to week 8. RESULTS Mean age was 12.4 years and 95% of patients were on a statin. Baseline LDL-C levels were 160.0-188.9 mg/dL and free PCSK9 was 186.4-201.7 ng/mL across the cohorts. At week 8, the higher dose cohorts (2 and 4) demonstrated the greatest reductions in LDL-C (-46% and -45%, respectively). Free PCSK9 levels were lowest at week 8 in cohorts 2 and 4 (42.2 ng/mL and 8.6 ng/mL, respectively). Adverse events were reported in 50-90% of patients across the cohorts, and 2 patients discontinued due to adverse events. CONCLUSIONS In pediatric HeFH patients, LDL-C reductions were greatest in the higher dose cohorts. Alirocumab was generally well tolerated at all doses.
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Circulatory and prostatic tissue lipidomic profiles shifts after high-dose atorvastatin use in men with prostate cancer.
Raittinen, P, Niemistö, K, Pennanen, E, Syvälä, H, Auriola, S, Riikonen, J, Lehtimäki, T, Ilmonen, P, Murtola, T
Scientific reports. 2020;(1):12016
Abstract
Prostate cancer patients using cholesterol-lowering statins have 30% lower risk of prostate cancer death compared to non-users. The effect is attributed to the inhibition of the mevalonate pathway in prostate cancer cells. Moreover, statin use causes lipoprotein metabolism changes in the serum. Statin effect on serum or intraprostatic lipidome profiles in prostate cancer patients has not been explored. We studied changes in the serum metabolomic and prostatic tissue lipidome after high-dose 80 mg atorvastatin intervention to expose biological mechanisms causing the observed survival benefit. Our randomized, double-blind, placebo-controlled clinical trial consisted of 103 Finnish men with prostate cancer. We observed clear difference in post-intervention serum lipoprotein lipid profiles between the study arms (median classification error 11.7%). The atorvastatin effect on intraprostatic lipid profile was not as clear (median classification error 44.7%), although slightly differing lipid profiles by treatment arm was observed, which became more pronounced in men who used atorvastatin above the median of 27 days (statin group median classification error 27.2%). Atorvastatin lowers lipids important for adaptation for hypoxic microenvironment in the prostate suggesting that prostate cancer cell survival benefit associated with statin use might be mediated by both, local and systemic, lipidomic/metabolomic profile changes.
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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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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.