Reduction In Risk Of Cardiovascular Events Research Articles

Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events

Abstract Background Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe, bempedoic acic, and proprotein convertase subtilisin/kexin type 9 (PCSK-9) (synthase-) inhibitors allow for the reduction in LDL-cholesterol in addition to statin therapy. Purpose We aimed to perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. In specific, we evaluated the potential influence of duration of follow-up on the association with mortality endpoints. Methods We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe, bempedoic acid, Bococizumab, Alirocumab, Evolocumab, Inclisiran in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of August 2023, were included. We made our search specific and sensitive using Medical Subject Headings terms and free text and considered studies published in English language. Search terms used were : "Bempedoic Acid" or "Bococizumab" or "Alirocumab" or "Evolocumab" or "Ezetimibe" or "Inclisiran" and "statin" and "cardiovascular events". Results A total of 123,785 patients from 15 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, ODYSSEY LONG TERM, EWTOPIA 75, PACMAN-AMI, RACING, SIPRE I, SPIRE II, OSLER-1 and OSLER-2, CLEAR HARMONY, CLEAR OUTCOMES, CLEAR SERENITY, CLEAR WISDOM) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 19% risk reduction in cardiovascular events (OR [95%CI]: 0.81 [0.75; 0.86]). Effect sizes were similar for myocardial infarction (0.81 [0.74; 0.89]) and even more pronounced for ischemic stroke (0.77 [0.70; 0.84]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.99 [0.93; 1.04]). Stratifying by follow-up duration of < vs. ≥ 3 years, no improvement in all-cause mortality was observed in both groups (<3 years: 1.04 [0.93; 1.17]; ≥3 years: 0.97 (0.88; 1.06). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown). Conclusion Intensified LDL-lowering therapy with ezetimibe, bempedoic acic or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. A potential survival benefit was also not observed in studies with follow-up duration of ≥ 3 years.

Early, Intensive and Persistent Lipid-Lowering Therapy for Secondary Prevention of Acute Coronary Syndrome.

Early and intensive low-density lipoprotein (LDL-C)-lowering therapy plays important roles in secondary prevention of acute coronary syndrome (ACS), but the treatment period for further clinical benefit remains undefined. This single-center, retrospective study explored LDL-C trajectory after ACS and its associations with subsequent cardiovascular events (CVE). In 831 patients with ACS, we evaluated LDL-C reduction during the first 2 months post-ACS as an index of early intervention and the area over the curve for LDL-C using 70 mg/dl as the threshold in the next 6 months (AOC-70) as a persistent intensity index. Patients were followed for a median of 3.0 (1.1-5.2) years for CVE, defined as the composite of cardiovascular death, non-fatal myocardial infarction, angina pectoris requiring revascularization, cerebral infarction, and coronary bypass grafting. LDL-C decreased from baseline to 2 months post-ACS (107±38 mg/dl to 78±25 mg/dl, p＜0.001) through high-intensity statin prescription (91.8%), while achieving rates of LDL-C ＜70 mg/dl at 2 months remained only 40.2% with no significant changes thereafter. During the follow-up period, CVE occurred in 200 patients. LDL-C reduction during the first 2 months and AOC-70 in the next 6 months were both associated with subsequent CVE risk (sub-HR [hazard ratio] [95% confidence interval]: 1.48 [1.16-1.89] and 1.22 [1.05-1.44]). Furthermore, early intervention followed by persistently intensive LDL-C-lowering therapy resulted in further CVE risk reduction. The present study observed that achieving early and intensive LDL-C reduction within the first two months after ACS and maintaining it for the next six months suppressed subsequent CVE risk, suggesting the importance of early, intensive, and persistent LDL-C-lowering therapy in the secondary prevention of ACS.

For which patients do the latest lipid lowering treatments reduce cardiovascular events?

Dyslipidemia is a modifiable risk factor for cardiovascular diseases. Recommendations are based on achieving LDL-C target levels, but it is essential to assess the benefits of intensifying lipid-lowering therapy in terms of absolute risk reduction of cardiovascular events across different risk groups. Current data on the absolute benefits of the latest lipid-lowering treatments are more limited in comparison with statins. A recent analysis showed that adding a second lipid-lowering treatment only reduces the absolute cardiovascular risk in patients at very high and high cardiovascular risk, without a substantial benefit in patients at moderate or low cardiovascular risk, as mentioned in the recent recommendations free of conflict of interest and published in the British Medical Journal.

Traditional Chinese medicine lowering lipid levels and cardiovascular events across baseline lipid levels among coronary heart disease: a meta-analysis of randomized controlled trials.

Dyslipidemia is a critical driver in the development of coronary heart disease (CHD), which further exacerbates the risk of major adverse cardiovascular events (MACEs). Chinese herbal medicine (CHM) plays an important role in the regulation of lipid levels and improvement of prognosis. However, few systematic reviews report whether the efficacy of CHM therapy for regulating lipid levels and lowering cardiovascular events is associated with baseline lipid levels. Randomized controlled trials assessing efficacy of CHM for lipid profiles and MACEs among patients with CHD were searched in six databases. Two authors independently extracted studies according to a predesigned form. Cochrane risk of bias tool and Grading of Recommendations Assessment, Development, and Evaluation system were used to assess the methodological quality of the included studies. The primary outcomes were blood lipid levels and MACEs including cardiovascular mortality, non-fatal myocardial infarction, revascularization, angina pectoris, heart failure, and non-fatal stroke across baseline lipid levels. The secondary outcomes were individual components of the primary outcomes. A total of 23 trials with 7,316 participants were included in this study. Altogether 377 cardiovascular events occurred in 3,670 patients in the CHM group, while 717 events occurred in 3,646 patients in the Western medicine-alone group. Compared with the Western medicine alone, additional CHM significantly lowered low-density lipoprotein cholesterol (LDL-C) [MD = -0.46, 95% CI (-0.60 to -0.32), P < 0.00001, I 2 = 96%]. The risk reduction in MACEs associated with CHM vs. Western medicine therapy was 0.52 [95% CI (0.47-0.58), P < 0.00001, I 2 = 0%], but varied by baseline LDL-C level (P = 0.03 for interaction). Triglycerides (TG) level was also significantly lowered by additional CHM vs. Western medicine alone [MD = -0.27, 95% CI (-0.34 to -0.20), P < 0.00001, I 2 = 81%], and risk reduction for MACEs also varied with baseline TG, with greater risk reduction in higher baseline TG subgroups (P = 0.03 for interaction). Similar results were observed with total cholesterol and high-density lipoprotein cholesterol. Compared with Western medicine alone, additional CHM was associated with lower risk of cardiovascular events and improvement of lipid profiles. Risk reduction for cardiovascular events was associated with baseline LDL-C and TG levels. https://www.crd.york.ac.uk/PROSPERO, identifier CRD42023425791.

Impact of Hypomethylating Agents on Cardiovascular Disease Risk Among Patients with Myelodysplastic Syndromes

Introduction: The association between clonal hematopoiesis (CH) and cardiovascular disease (CVD) risk has drawn attention to cardiovascular outcomes in myelodysplastic syndromes (MDS). CVD accounts for 25% of deaths in MDS, potentially via CH-mediated accelerated atherosclerosis from inflammatory vascular responses. We previously demonstrated that MDS was independently associated with increased risk of CVD in older adults from SEER-Medicare. We subsequently hypothesized that treatment with hypomethylating agents (HMA) could reduce CVD risk by ameliorating CH clones and reducing the inflammation. In this study, we aimed to define the impact of HMA on incident cardiovascular events among older adults with MDS. Methods: We identified subjects ≥66 years diagnosed with MDS from 2007 to 2017 in SEER-Medicare. Exclusion criteria including lacking continuous Medicare parts A, B, and D, enrolled in HMO, or incomplete follow-up. Demographics included age, sex, race, rurality, socioeconomic quintile, marital status, and geographic region. Baseline CVD risk factors, defined from ICD-9/10 codes, included hypertension, hyperlipidemia, diabetes, atrial fibrillation, pre-existing cardiac disease, obesity, and smoking. MDS factors, defined using HCPCS codes, ICD-O-3 codes and prescription records, included MDS subtype and histologic risk stratification, transfusion dependence and treatment with hypomethylating agents (HMA), lenalidomide, or erythropoietin-stimulating agents (ESA) as time-varying variables. Incident CVD was defined as new myocardial infarction (MI) and/or ischemic stroke occurring after MDS diagnosis, using published ICD-9/10 algorithms. We controlled for confounding using 2 complementary analytic approaches. First, we assessed the association between HMA use and CVD using propensity score adjusted cause-specific competing risk Cox hazard models with death as competing risk, Second, we used a case-crossover design with conditional logistic regression, in which subjects with CVD served as their own controls, using a 3-month HMA treatment window and a control period 6 months prior to the incident event. Results: We identified a cohort of 15,227 eligible patients with MDS. Of these, 1,125 patients had an MI and/or ischemic stroke within 1 year before MDS diagnoses and were excluded. We analyzed 14,102 MDS patients, with median age 82 years (IQR 77 - 86), who were predominantly male (53.8%), non-Hispanic white (88.6%), and from urban/suburban areas (86.2%). MDS was of low, intermediate, and high histologic risk in 14.7%, 72.8%, and 12.5%, respectively, and 28.6% were transfusion dependent. Pre-existing CVD risk factors at time of MDS diagnosis were present in 12,538 patients, with baseline cardiovascular risk defined as low, intermediate, and high in 11.1%, 32.3%, and 56.6% of the cohort. The cumulative incidences of MI, ischemic stroke and composite CVD events were 11.3%, 10.6% and 20.4%, respectively. The propensity score (PS) conditional probability for being treated with HMA included demographic variables, CVD risk factors, MDS histology and transfusion dependence. Our PS model adequately predicted HMA treatment propensity (AUC 0.76). Cause-specific regression with death as competing risk, adjusted for PS and other MDS-specific treatments (ESA and lenalidomide), showed no significant effect of HMA on the risk of composite CVD events, MI, or ischemic stroke (Table 1). Conditional logistic regression in the case-crossover analysis of 1,907 patients with composite CVD events showed no significant effect of HMA. Results were similar for analysis of patients with MI and ischemic stroke (Table 2). Conclusions: No study has previously investigated the effect of HMA therapy on cardiovascular outcomes in patients with MDS. We demonstrate that HMA therapy is not associated with a significant risk reduction in cardiovascular events among patients with MDS patients from the SEER-Medicare database. These results show that HMA therapy is unlikely to reduce cardiovascular mortality and underscore the need for alternative therapeutic strategies targeting cardiovascular health patients with MDS.

Clinical effectiveness of second-line antihyperglycemic drugs on major adverse cardiovascular events: An emulation of a target trial.

The cardiovascular benefits of multiple antihyperglycemic drugs as add-on therapies to metformin in the real-practice are unclear. This study aimed to directly compare major adverse cardiovascular events (CVE) associated with these multiple drugs. An emulation of a target trial was conducted using a retrospective-cohort data of type 2 diabetes mellitus (T2DM) prescribed with second-line drugs on top of metformin, including sodium-glucose cotransporter 2 inhibitors (SGLT2i), dipeptidyl peptidase-4 inhibitors (DPP4i), thiazolidinediones (TZD) and sulfonylureas (SUs). We applied inverse probability weighting and regression adjustment using intention-to-treat (ITT), per-protocol analysis (PPA) and modified ITT. Average treatment effects (ATE) were estimated using SUs as the reference. Among 25,498 patients with T2DM, 17,586 (69.0%), 3,261 (12.8%), 4,399 (17.3%), and 252 (1.0%) received SUs, TZD, DPP4i, and SGLT2i. Median follow-up time was 3.56 (1.36-7.00) years. CVE was identified in 963 patients. The ITT and modified ITT approaches showed similar results; the ATE (i.e., the difference of CVE risks) for SGLT2i, TZD, and DPP4i compared to SUs were -0.020(-0.040, -0.0002), -0.010(-0.017, -0.003), and -0.004(-0.010, 0.002), respectively, indicating 2% and 1% significant absolute risk reduction in CVE in SGLT2i and TZD compared to SUs. These corresponding effects were also significant in the PPA with ATEs of -0.045(-0.060, -0.031), -0.015(-0.026, -0.004), and -0.012(-0.020, -0.004). In addition, SGLT2i had 3.3% significant absolute risk reduction in CVE relative to DPP4i. Our study demonstrated benefits of SGLT2i and TZD in reducing CVE in T2DM patients compared to SUs when added to metformin.

Patient Selection for Pemafibrate Therapy to Prevent Adverse Cardiovascular Events.

Background: pemafibrate is a newly-introduced selective peroxisome proliferator-activated receptor-α modulator, which decreases serum triglyceride levels with few drug-related adverse events and may reduce the risk of adverse cardiovascular events in carefully selected patients with hypertriglyceridemia. We aimed to understand which specific cohorts may benefit or not from pemafibrate therapy for adverse cardiovascular event risk reduction. Methods: patients with hypertriglyceridemia at baseline received pemafibrate therapy for two years or until October 2022. The factors that were associated with an increased risk of adverse cardiovascular events, defined as heart failure hospitalization, stroke, and acute coronary syndromes, were investigated. Results: a total of 121 patients (median 62 years, 88 men) remained on pemafibrate therapy for a median of 566 days without any drug-related adverse events. During a 3-month therapeutic period, triglyceride levels improved significantly from 302 (205, 581) mg/dL to 178 (117, 253) mg/dL (p < 0.001). During the overall therapeutic period, there were nine cardiovascular events. Comorbid chronic heart failure, comorbid coronary disease, and a lower pemafibrate dosing were independently associated with the primary endpoint (p < 0.05 for all). Those with multiple risk factors (N = 30) had a significantly higher cumulative incidence of the primary endpoint as compared with others (27% versus 3%, p < 0.001). Conclusion: pemafibrate significantly improves hypertriglyceridemia. A higher dose of pemafibrate should be considered to reduce the risk of adverse cardiovascular events, particularly in patients with chronic heart failure or coronary disease.

The association between dyslipidaemia treatment and the risk of clinical events in edoxaban-treated patients with atrial fibrillation: insights from the 2-year follow-up of ETNA-AF-Europe

Abstract Background/Introduction Dyslipidaemia is a major risk factor for cardiovascular (CV) events. This increased risk can be attenuated with lipid-lowering therapies (LLT), such as statins, which are associated with a relative risk reduction of CV events of 22% for each 1 mmol/L reduction in low-density lipoprotein cholesterol. Purpose To explore the association between use of LLT and clinical outcomes in routine practice patients with atrial fibrillation (AF) receiving edoxaban. Methods ETNA-AF-Europe is a prospective, multi-centre, post-authorisation, observational cohort study conducted in 825 centres, enrolling routine practice patients with AF treated with edoxaban in 10 European countries. This registry is still ongoing and patients are to be followed-up annually for 4 years after enrollment. In the current sub-study, on the now available first 2 years of follow-up, patients were categorised by use of LLT at baseline. We used Cox proportional hazards models to determine the associations between LLT use and adverse clinical events, including the composite of any stroke and systemic embolic events (SEE), major bleeding, and death, after adjusting for confounding factors at baseline. Results Of 13,133 patients with AF, 36.3% (n=4761) used LLT at baseline. Among those receiving LLT, 90.7% received statins only and 3.6% received combination therapy with a statin. Most patients in both treatment groups were 65 years or older and had one or more CV-risk factors aside from a history of AF. Patients receiving LLT were older and had a higher prevalence of CV co-morbidities (including diabetes, hypertension, peripheral artery disease and coronary heart disease) than those who did not receive LLT (Table 1). After correction for confounders, treatment with LLT was associated with a significantly lower rate of any stroke or SEE (HR: 0.61; 95% CI: 0.42–0.88), ischaemic stroke (HR: 0.54; 95% CI: 0.35–0.83), all-cause death (HR: 0.73; 95% CI: 0.63–0.85) and CV-death (HR: 0.73; 95% CI: 0.60–0.90), but not with bleeding events or myocardial infarction (Figure 1). Conclusion These findings suggest a protective effect of LLT on the risk of stroke in anticoagulated patients with AF, although an overall better CV risk management in these patients probably contributed to this reduced risk. Notably, both mono- and combination-LLT were seemingly underused in our cohort, highlighting the potential for further reductions of CV risks in the AF patients seen in our clinics. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): This research was funded by Daiichi Sankyo Europe.

†A Cross-Study Comparison Investigating the Effect of CSL112 (Apolipoprotein A-I [Human]) on Cholesterol Efflux Capacity (Encore ACC 2022)

Lead Author's Financial Disclosures Nothing to disclose. Study Funding CSL Behring, LLC. Background/Synopsis Following an acute myocardial infarction (AMI), patients are at high risk of secondary major adverse cardiovascular events (MACE) that are associated with increased morbidity and mortality. Cholesterol efflux capacity (CEC), a key marker of high- density lipoprotein (HDL) function, is inversely correlated with the incidence of MACE. CSL112 (human-derived apolipoprotein A-I [apoA-I]) is a novel agent in Phase III development, aimed to reduce the risk of MACE following AMI. In Phase I and II clinical trials, CSL112 has demonstrated significant increases in CEC; these studies were conducted across different patient populations, including healthy individuals of different ethnicities known to have variations in lipid metabolism, and have shown CSL112 is well tolerated with a favorable safety profile. Objective/Purpose This cross-study analysis aims to evaluate the pharmacokinetic (PK) and pharmacodynamic (PD) properties of CSL112 across prior clinical studies, to assess the impact of ethnicity and disease status on apoA-I exposure and CEC. Methods Data from five CSL112 clinical trials were combined: single and multiple ascending dose Phase I studies in healthy volunteers (N=57 and N=36, respectively), a Phase I Japanese ethno-bridging study (N=52), a Phase IIa study in subjects with stable atherosclerotic disease (N=45), and a Phase IIb study in post-AMI subjects AEGIS-I (N=1267). Dose-normalized and baseline corrected PK parameters and CEC responses were compared between the subpopulations. Results Comparison of PK parameters confirmed that the dose-normalized exposures (measured by the maximum concentration [Cmax] and area under the curve [AUC]) of apoA-I were similar across healthy Caucasian and Japanese subjects, subjects with stable atherosclerosis, and subjects post-AMI. PD parameters were also comparable; dose-normalized baseline-corrected CEC were comparable between Japanese, Caucasian, and post-AMI subjects. In addition, following intravenous infusions of 6 g CSL112, similar fold elevations of apoA-I in Japanese, Caucasian and post-AMI subjects (median 2.08, 2.33, 2.08-fold increase, respectively) and total CEC (median of 2.74, 2.92 and 2.55 fold, respectively) were observed. Conclusions CSL112 induces comparable, immediate and robust increases in key biomarkers across different subpopulations. The comparable distribution range and patterns of CSL112 PK/PD parameters between the subpopulations suggests that disease status or ethnicity do not confer any clinically relevant differences on apoA-I exposure and CEC following CSL112 infusion. These results support the use of a fixed 6g dose in the ongoing global Phase III trial (AEGIS-II), investigating the impact of CSL112 on cardiovascular event risk reduction post- myocardial infarction. Nothing to disclose.

548 Colchicine in patients with coronary artery disease: a meta-analysis of randomized trials

Abstract Aims The aim of this study was to provide a systematic appraisal of the effects of colchicine treatment on cardiovascular outcomes, adverse events, and mortality in patients with coronary artery disease. Methods and results We performed a meta-analysis of randomized controlled trials (RCTs) that compared add-on colchicine to standard treatment vs. standard treatment in patients with coronary artery disease. Mixed-effects Poisson regression model with random intervention effects was used to estimate the pooled incidence rate ratios (IRR) with 95% confidence intervals (CI). The number needed to treat for an additional beneficial outcome (NNTB) or for an additional harmful outcome (NNTH) were calculated. Prespecified subgroup analyses according to colchicine dose (e.g. &amp;lt;1 mg/daily or ≥ 1 mg/daily) and the type of clinical syndrome [e.g. acute coronary syndrome (ACS) or chronic coronary syndrome (CCS)] were performed. Ten RCTs were identified, including 12 819 participants with a median follow-up of 6 months. Add-on colchicine, compared to standard treatment, was associated with a lower risk of major adverse cardiovascular events (IRR: 0.69, 95% CI: 0.60–0.79, NNTB = 28), myocardial infarction (IRR: 0.77, 95% CI: 0.64–0.93, NNTB = 95), and ischaemic stroke (IRR: 0.48, 95% CI: 0.30–0.76, NNTB = 155), while it was associated with a higher risk of gastrointestinal adverse events (IRR: 1.69, 95% CI: 1.12–2.54, NNTH = 10). Colchicine use did not affect all-cause death (IRR: 1.09, 95% CI: 0.85–1.40), or cardiovascular death (IRR: 0.75, 95% CI: 0.51–1.12), while it was associated with a higher risk of non-cardiovascular death (IRR: 1.45, 95% CI: 1.04–2.02, NNTH = 396). In the subgroup analysis of colchicine dose, a significant interaction was found with the risk of gastrointestinal adverse events (IRR: 1.03, 95% CI: 0.91–1.15, in patients receiving colchicine &amp;lt;1 mg/daily; IRR: 2.91, 95% CI: 1.91–4.44, in patients receiving colchicine ≥1 mg/daily, p for interaction &amp;lt;0.0001), while there was no evidence for a modification of treatment effect for the remaining endpoints. In the subgroup analysis of the clinical syndrome, there was little evidence for an interaction with the risk of myocardial infarction (IRR: 0.91, 95% CI: 0.71–1.18, in patients presenting with ACS; IRR: 0.65, 95% CI: 0.50–0.84, in patients presenting with CCS, p for interaction = 0.07), while there was no evidence for a modification of treatment effect for the remaining endpoints. Conclusions This meta-analysis of RCT provides evidence for a significant clinical benefit of add-on colchicine in terms of risk reduction of cardiovascular events in patients with coronary artery disease, that largely outweigh a potential harmful effect of colchicine on the risk of non-cardiovascular death. Colchicine is associated with a higher risk of gastrointestinal adverse effects that can be prevented by using a low-dose regimen (e.g. &amp;lt;1 mg daily).

LDL cholesterol: lower, faster, younger?

Findings from recent clinical trials of LDL cholesterol lowering suggest continued benefits at lower concentrations than those previously considered acceptable. In The Lancet Diabetes & Endocrinology, Nelson Wang and colleagues emphasise this concept in their large meta-analysis 1 Wang N Fulcher J Abeysuriya N et al. Intensive LDL cholesterol-lowering treatment beyond current recommendations for the prevention of major vascular events: a systematic review and meta-analysis of randomised trials including 327 037 participants. Lancet Diabetes Endocrinol. 2020; 8: 36-49 Summary Full Text Full Text PDF PubMed Scopus (62) Google Scholar that incorporates results of 52 randomised controlled trials of cholesterol-lowering drugs with a primary composite cardiovascular endpoint. Across three mechanistically distinct drug classes—statins, ezetimibe, and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors—there was a direct linear association between pharmacological LDL cholesterol lowering and relative risk reduction in cardiovascular events. A 1 mmol/L reduction in LDL cholesterol corresponded to a relative risk reduction of 19%, irrespective of baseline LDL cholesterol concentration or drug class used. Although the analysis used average LDL cholesterol concentrations in the treatment versus control groups, rather than individual participant level data, it still provides compelling evidence for the cardiovascular benefit of LDL cholesterol reduction, with no apparent lower threshold for additional benefit. Intensive LDL cholesterol-lowering treatment beyond current recommendations for the prevention of major vascular events: a systematic review and meta-analysis of randomised trials including 327 037 participantsFor each 1 mmol/L LDL cholesterol lowering, the risk reduction of major vascular events is independent of the starting LDL cholesterol or the presence of diabetes or chronic kidney disease. Patients at lower cardiovascular risk and younger age might have a similar relative reduction in risk with LDL-cholesterol lowering therapies and future studies should investigate the potential benefits of earlier intervention. Full-Text PDF

P5015Efficacy of lipid lowering therapy beyond statins to prevent cardiovascular events: A meta-analysis

Abstract Background Lipid lowering therapy is a key cornerstone in secondary prevention of patients with coronary artery disease. However, only a minority of patients with statin therapy reach LDL thresholds as suggested by the ESC. Ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK-9) inhibitors allow for reduction in LDL-cholesterol in addition to statin therapy. Purpose To perform a meta-analysis of existing trials, evaluating how lipid lowering therapy beyond statins impacts cardiovascular outcome. Methods We performed a systematic search using the Pubmed, Cochrane, SCOPUS, and Web of Science databases for studies, evaluating the impact of an intensified lipid lowering therapy via ezetimibe or PCSK-9 inhibitor in addition to statin therapy compared to statin therapy alone. Manuscript and congress presentations, published until 1st of November 2018, were included. We made our search specific and sensitive using Medical Subject Headings terms and free text and considered studies published in English language. Search terms used were “ezetimibe”, “evolocumab”, “alirocumab”, or “bococizumab” and “cardiovascular events”. Results A total of 100,610 patients from 9 randomized controlled trials (IMPROVE-IT, FOURIER, ODYSSEY Outcomes, SIPRE I, SPIRE II, ODYSSEY LONG TERM, OSLER-1 and OSLER-2, HIJ-PROPER) were included. Treatment with ezetimibe or a PCSK-9 inhibitor was associated with a 18% risk reduction in cardiovascular events (OR [95% CI]: 0.82 [0.75–0.89]). Effect sizes were similar for myocardial infarction (0.84 [0.76–0.92]) and even more pronounced for ischemic stroke (0.77 [0.67–0.83]). In contrast, all-cause mortality was not improved by the intensified lipid lowering therapy (0.94 [0.85–1.05]). No relevant heterogeneity and inconsistency between groups was present in all analyses (detailed data not shown). Comparing efficacy of LDL-reduction and relative risk redaction of cardiovascular events, a linear relationship was observed (figure). Figure 1. Correlation of reduction of LDL-cholesterol at one year with relative risk reduction (95% confidence interval) of cardiovascular events in included trials. Conclusion Intensified LDL-lowering therapy with ezetimibe or PCSK-9 inhibitors, in addition to statins, reduces the risk of myocardial infarction and stroke, however, does not impact overall mortality. There is a linear relationship between LDL reduction and cardiovascular risk reduction, confirming the beneficial effects of LDL lowering therapy beyond statins in secondary prevention.

23-valent pneumococcal polysaccharide vaccine improves survival in dialysis patients by preventing cardiac events

BackgroundImmunodeficient patients are recommended to receive pneumococcal vaccination. However, there is limited evidence showing effectiveness of the polysaccharide vaccine. Polysaccharide vaccination has shown an association with cardiovascular event risk reduction. We assessed the efficacy of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) in relation to the risk of hospitalization and death due to pneumonia and acute cardiac events. MethodsThe medical records of all dialysis patients attending our 8 study centers in 2010 were studied, and we selected 1038 consecutive patients. One-to-one propensity score matching was used to correct for potential selection bias in a PPSV23-vaccinated group versus a non-vaccinated group, and a total of 510 patients were identified for outcome analysis. Time to first admission, or deaths due to all-cause pneumonia or cardiac events until 2015 were compared between both groups. ResultsThe all-cause death rate was significantly decreased in the PPSV23-vaccinated group, (hazard ratio [HR] 0.62, 95% confidence interval [CI]; 0.46–0.83, P = 0.002). All-cause death was considered to be a competing risk for the other outcomes. Further outcomes were evaluated by competing risk analysis adjusting for mortality. There was no statistically significant difference in the hospitalization rate for pneumonia; however, the hospitalization rate due to cardiac events was significantly lower in the PPSV23-vaccinated group than in the non-vaccinated group (HR 0.44, 95% CI; 0.20–0.96, P = 0.040). There was no statistically significant difference in the death rate due to pneumonia; however, the rate of cardiac death was significantly lower in the PPSV23-vaccinated group than in the non-vaccinated group (HR 0.36, 95% CI; 0.18–0.71, P = 0.003). ConclusionsThe PPSV23 vaccination is associated with a good prognosis and a low-risk of cardiac events in dialysis patients; however, there was no evidence indicating enhanced protective efficacy against pneumonia, suggesting the PPSV23 vaccination might improve the prognosis by directly preventing cardiovascular events.

A Multicenter, Randomized, Placebo-Controlled Trial of Atorvastatin for the Primary Prevention of Cardiovascular Events in Patients With Rheumatoid Arthritis.

ObjectiveRheumatoid arthritis (RA) is associated with increased cardiovascular event (CVE) risk. The impact of statins in RA is not established. We assessed whether atorvastatin is superior to placebo for the primary prevention of CVEs in RA patients.MethodsA randomized, double‐blind, placebo‐controlled trial was designed to detect a 32% CVE risk reduction based on an estimated 1.6% per annum event rate with 80% power at P < 0.05. RA patients age >50 years or with a disease duration of >10 years who did not have clinical atherosclerosis, diabetes, or myopathy received atorvastatin 40 mg daily or matching placebo. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, transient ischemic attack, or any arterial revascularization. Secondary and tertiary end points included plasma lipids and safety.ResultsA total of 3,002 patients (mean age 61 years; 74% female) were followed up for a median of 2.51 years (interquartile range [IQR] 1.90, 3.49 years) (7,827 patient‐years). The study was terminated early due to a lower than expected event rate (0.70% per annum). Of the 1,504 patients receiving atorvastatin, 24 (1.6%) experienced a primary end point, compared with 36 (2.4%) of the 1,498 receiving placebo (hazard ratio [HR] 0.66 [95% confidence interval (95% CI) 0.39, 1.11]; P = 0.115 and adjusted HR 0.60 [95% CI 0.32, 1.15]; P = 0.127). At trial end, patients receiving atorvastatin had a mean ± SD low‐density lipoprotein (LDL) cholesterol level 0.77 ± 0.04 mmoles/liter lower than those receiving placebo (P < 0.0001). C‐reactive protein level was also significantly lower in the atorvastatin group than the placebo group (median 2.59 mg/liter [IQR 0.94, 6.08] versus 3.60 mg/liter [IQR 1.47, 7.49]; P < 0.0001). CVE risk reduction per mmole/liter reduction in LDL cholesterol was 42% (95% CI −14%, 70%). The rates of adverse events in the atorvastatin group (n = 298 [19.8%]) and placebo group (n = 292 [19.5%]) were similar.ConclusionAtorvastatin 40 mg daily is safe and results in a significantly greater reduction of LDL cholesterol level than placebo in patients with RA. The 34% CVE risk reduction is consistent with the Cholesterol Treatment Trialists’ Collaboration meta‐analysis of statin effects in other populations.

FACTORS ASSOCIATED WITH AN INCREASED SYSTOLIC BLOOD PRESSURE VISIT- TO-VISIT VARIABILITY IN A TERTIARY HEALTH CARE CENTER

Objective: Identify factors associated with an increased systolic blood pressure visit to visit variability in a “real-life” setting. Design and method: The study was observational, and retrospective. We included 2436 hypertensive outpatients, followed at our tertiary health care center, who had at least 8 visits with blood pressure readings. Epidemiological, clinical and therapeutic data were extracted and analyzed. Systolic blood pressure visit to visit variability was defined as the standard deviation around the mean systolic blood pressure of the 8 recordings. Results: The mean age of the population was 63.7 ± 10.9 years, and 55.7% of the patients were men. The proportions of diabetes, smoking, dyslipidemia and history of major cardiovascular events were 32.4%, 28.6%, 39.9% and 22.6% respectively. The mean blood pressure was 157.2 ± 11.7 / 90.8 ± 8.3 mmHg. The proportions of patients receiving one, two, three or more antihypertensive drugs at time of inclusion were 19.6%, 59.4% and 21% respectively. We found that age, systolic blood pressure, left ventricular hypertrophy, low eGFR, use of diuretics and use of beta-blockers were significantly associated with an increased systolic blood pressure variability. In a multiple regression analysis, the remaining independent factors were: age (p = 0.001), low eGFR (p = 0.003), use of diuretics (p = 0.0001) and treatment with beta-blockers (p = 0.0001). Conclusions: Among factors affecting blood pressure visit to visit variability in our hypertension unit, the most deleterious are related to the type of drug prescribed, suggesting that limiting the use of these medications, at least in the first step, could result in a risk reduction of cardiovascular events linked to blood pressure visit to visit variability.

The effect of dapagliflozin treatment on epicardial adipose tissue volume

BackgroundGlycosuria produced by sodium–glucose co-transporter-2 (SGLT-2) inhibitors is associated with weight loss. SGLT-2 inhibitors reportedly might reduce the occurrence of cardiovascular events. Epicardial adipose tissue (EAT) is a pathogenic fat depot that may be associated with coronary atherosclerosis. The present study evaluated the relationship between an SGLT-2 inhibitor (dapagliflozin) and EAT volume.MethodsIn 40 diabetes mellitus patients with coronary artery disease (10 women and 30 men; mean age of all 40 patients was 67.2 ± 5.4 years), EAT volume was compared prospectively between the dapagliflozin treatment group (DG; n = 20) and conventional treatment group (CTG; n = 20) during a 6-month period. EAT was defined as any pixel that had computed tomography attenuation of − 150 to − 30 Hounsfield units within the pericardial sac. Metabolic parameters, including HbA1c, tumor necrotic factor-α (TNF-α), and plasminogen activator inhibitor-1 (PAI-1) levels, were measured at both baseline and 6-months thereafter.ResultsThere were no significant differences at baseline of EAT volume and HbA1c, PAI-1, and TNF-α levels between the two treatment groups. After a 6-month follow-up, the change in HbA1c levels in the DG decreased significantly from 7.2 to 6.8%, while body weight decreased significantly in the DG compared with the CTG (− 2.9 ± 3.4 vs. 0.2 ± 2.4 kg, p = 0.01). At the 6-month follow-up, serum PAI-1 levels tended to decline in the DG. In addition, the change in the TNF-α level in the DG was significantly greater than that in the CTG (− 0.5 ± 0.7 vs. 0.03 ± 0.3 pg/ml, p = 0.03). Furthermore, EAT volume significantly decreased in the DG at the 6-month follow-up compared with the CTG (− 16.4 ± 8.3 vs. 4.7 ± 8.8 cm3, p = 0.01). Not only the changes in the EAT volume and body weight, but also those in the EAT volume and TNF-α level, showed significantly positive correlation.ConclusionTreatment with dapagliflozin might improve systemic metabolic parameters and decrease the EAT volume in diabetes mellitus patients, possibly contributing to risk reduction in cardiovascular events.

A fixed-dose combination of bisoprolol and amlodipine in daily practice treatment of hypertension: Results of a non-investigational study in the Czech Republic

Summary Objective: This non-investigational study with the primary goal to assess patient adherence to the fixed dose combination (FDC) of bisoprolol and amlodipine in daily practice was carried out in six countries in Eastern Europe, in Czech Republic, Hungary, Poland, Romania, Serbia and Slovakia. In this paper, the results of 740 patients recruited in Czech Republic are presented. Secondary objectives included the assessment of blood pressure, pulse pressure values and heart rate. Material and Methods Patients eligible for recruitment were over 18 years of age, had essential hypertension, had already been switched from a free combination of bisoprolol 5–10mg/d and amlodipine 5–10mg/d to the FDC at least 4 weeks prior to recruitment, and gave informed consent. Women in childbearing age were under reliable contraception. Exclusion criteria included pregnancy, lactation, any contraindication to the FDC according to the local label and any other antihypertensive medication. The primary target parameter was patient adherence under the FDC. Adherence was measured by tablet count (tablets taken divided by tablets prescribed, times 100). The definition was as follows: excellent >90%, good 76-90%, moderate 51-75%, bad <50%. The study hypothesis was that at least 90% of the patients showed good to excellent adherence. All other patient data, clinical findings and laboratory values were recorded upon availability at study start and after 6 months. Results There were more male (383, 52%) than female (357, 48%) patients. The mean age was 58.8 years with a Q1 – Q3 interval of 51 to 68 years. The youngest patient was 23 years and the oldest 95 years old. All patients had been pretreated once daily with a free combination of bisoprolol (mean 5.8mg) and amlodipine (mean 5.9mg). In most patients, the doses were not changed at the switch to the FDC or later during the study, resulting in a mean of 6.2mg for bisoprolol and 5.9mg for amlodipine. Over the 6 months of treatment, the adherence of 98% of the patients was good to excellent. Thus, the study expectation was more than met. Potentially due to the excellent adherence, there was a 12.1mmHg reduction in mean systolic and a 6.9mmHg reduction in mean diastolic blood pressure after 6 months compared to study start. The benefits of patient adherence on blood pressure control are confirmed by the improvement of the pulse pressure by an average of 59.1mmHg±13 at study start versus 54.1mmHg±10 after 6 month of treatment. Heart rate decreased by a mean of 5.6bpm. Only in 2 patients (0.3%), two adverse drug reactions probably related to the study medication were documented after 6 months: one case of hypotension and one case of edema. None of the adverse drug reactions (ADR) was considered serious and both patients fully recovered. Overall, the FDC of bisoprolol and amlodipine was well tolerated. The study results clearly show that the high adherence under the FDC of bisoprolol and amlodipine may contribute to better blood pressure control and, thus, to a better risk reduction for cardiovascular events.

Clinical significance of 'cardiometabolic memory': a systematic review of randomized controlled trials.

'Cardiometabolic memory' has been proposed based on clinical evidence to explain how, even after the cessation of a clinical trial, the superiority of one treatment over the outcome persists. To understand the cardiometabolic memory phenomenon, we performed a systematic review of randomized controlled trials (RCTs) using PubMed in August 2016. The search terms 'randomized controlled trial', 'post-trial follow-up' and 'diabetes, hypertension or dyslipidemia' were used, and articles published after the year 2000 were searched. We judged the memory phenomenon to be positive when the cardiovascular outcome at the end of the post-trial follow-up period in the intervention group was significantly superior even though the favorable control of a risk factor (blood glucose, blood pressure or lipid level) during the trial period was lost after the cessation of the intervention. Among 907 articles retrieved in the initial screening, 21 articles were judged as describing a positive memory phenomenon. Eight, six and seven of the articles concerned diabetes, hypertension and dyslipidemia, respectively. Transient intensive glucose lowering rather easily induced memory for the suppression of diabetic microangiopathies, while memory for the suppression of macroangiopathies tended to be first evident in the post-trial follow-up period. Transient intensive blood pressure lowering was generally effective in the formation of memory for the suppression of cardiovascular events and had an especially strong impact on risk reduction of chronic heart failure. Transient intensive LDL cholesterol lowering clearly had a long-term beneficial effect on risk reduction of cardiovascular events. Our systematic review revealed the clinical relevance of cardiometabolic memory.

Cardiovascular event risk assessment in psoriasis patients treated with tumor necrosis factor-α inhibitors versus methotrexate

Psoriasis is associated with increased risk for cardiovascular disease. To compare major cardiovascular event risk in psoriasis patients receiving methotrexate or tumor necrosis factor-α inhibitor (TNFi) and to assess TNFi treatment duration impact on major cardiovascular event risk. Adult psoriasis patients with ≥2 TNFi or methotrexate prescriptions in the Truven MarketScan Databases (Q1 2000-Q3 2011) were classified as TNFi or methotrexate users. The index date for each of these drugs was the TNFi initiation date or a randomly selected methotrexate dispensing date, respectively. Cardiovascular event risks and cumulative TNFi effect were analyzed by using multivariate Cox proportional-hazards models. By 12months, TNFi users (N=9148) had fewer cardiovascular events than methotrexate users (N=8581) (Kaplan-Meier rates: 1.45% vs 4.09%: P<.01). TNFi users had overall lower cardiovascular event hazards than methotrexate users (hazard ratio=0.55; P<.01). Over 24months' median follow-up, every 6months of cumulative exposure to TNFis were associated with an 11% cardiovascular event risk reduction (P=.02). Lack of clinical assessment measures. Psoriasis patients receiving TNFis had a lower major cardiovascular event risk compared to those receiving methotrexate. Cumulative exposure to TNFis was associated with a reduced risk for major cardiovascular events.

Dynamics of endothelial function violation in patients with arterial hypertension with moderate cardiovascular risk and antihypertensive therapy treatment influence

Aim. To assess the impact of one-year monitored different groups’ antihypertensive therapy on markers of endothelial dysfunction. Materials and methods. We examined 48 hypertensive patients with moderate cardiovascular risk. Among them: 1a subgroup took losartan potassium, 1b – standard antihypertensive drugs without sartans. During the year all patients except of general clinical examination were studied by such special clinical and laboratory parameters as concentration of endothelial dysfunction markers in serum (endothelin-1, thrombomodulin and von Willebrand factor). Results. With constant monitoring of pressure on the background of a statistically comparable levels of SBP in the subgroups at the beginning of the study (p<0.05), during the fourth visit SBP was significantly decreased in subgroup 1a compared with the control subgroup (p<0.05). Dynamics of DBP levels with antihypertensive therapy in both subgroups was also statistically significant (p<0.001, compared to baseline). Positive changes of lipid metabolism indices were observed during 12 months of monitoring in both subgroups of patients from the second visit (from p<0.05 to p<0.001), indicating a reduction of cardiovascular events risk. There is a significant difference of indicators with comparable baseline levels of ET-1 and vWF in subgroups (p<0.05) after a year of monitoring – in patients treated with losartan potassium, rates are lower than in the control subgroup. Thrombomodulin levels in the subgroup of patients treated with losartan potassium were significantly decreased in a year (p<0.05), whereas subgroup 1b on antihypertensive therapy without angiotensin II receptors antagonist using, this indicator almost has not changed. Reduction of all ED markers indicates the tendency to establishing of pro- and anti-platelet systems balance, especially expressed in patients who were treated with losartan potassium. Conclusion. Cardiovascular events risk reduction is caused by stabilization of blood pressure, indices of lipid profile lowering, the tendency to endothelial function improvement, especially with losartan potassium therapy.