Metabolic risk factors and effect of alirocumab on cardiovascular events after acute coronary syndrome: a post-hoc analysis of the ODYSSEY OUTCOMES randomised controlled trial.

BACKGROUND: Many patients with acute coronary syndrome have concurrent metabolic risk factors that affect risk of major adverse cardiovascular events (MACE). We aimed to assess the effects of the PCSK9 inhibitor alirocumab compared with placebo on MACE according to baseline metabolic risk factors. METHODS: We performed a post-hoc analysis of the ODYSSEY OUTCOMES trial, which was a multicentre, double-blind, randomised controlled trial done in 1315 hospitals and outpatient clinics in 57 countries. Patients aged 40 years or older with recent acute coronary syndrome (ie, in the past 1-12 months) and elevated concentrations of atherogenic lipoproteins, despite high-intensity or maximum-tolerated statin treatment, were eligible for enrolment. Between Nov 2, 2012, and Feb 9, 2017, patients were randomly assigned (1:1) to 75 mg alirocumab by subcutaneous injection every 2 weeks or matching placebo, beginning 1-12 months after acute coronary syndrome and were followed up for a median of 2·8 years (IQR 2·3-3·4). Patients and investigators were masked to group assignment and treatment dose adjustment. The primary outcome was a composite of death from coronary artery disease, non-fatal myocardial infarction, fatal or non-fatal ischaemic stroke, or unstable angina requiring hospital admission. Analysis of MACE according to an ordinal number of metabolic risk factors was done post hoc. Metabolic risk factors were defined as blood pressure of at least 130/85 mm Hg or treatment with antihypertensive medication, triglyceride concentration of at least 150 mg/dL, HDL cholesterol concentration less than 40 mg/dL for men and 50 mg/dL women, fasting plasma glucose concentration of at least 100 mg/dL or treatment with glucose-lowering medication, and BMI of at least 30 kg/m2. Risk of MACE and effect of alirocumab were assessed according to the number of metabolic risk factors. ODYSSEY OUTCOMES is registered with ClinicalTrials.gov, number NCT01663402. FINDINGS: Of 18 924 patients, 3882 (41%) of 9462 in the alirocumab group and 3859 (41%) of 9462 in the placebo group had three or more metabolic risk factors. In the placebo group, MACE incidence increased monotonically with each metabolic risk factor from 7·8% (no risk factors) to 19·6% (five risk factors; HR 1·18, 95% CI 1·13-1·24 per metabolic risk factor). Alirocumab decreased relative risk of MACE consistently across categories defined by the number of metabolic risk factors (pinteraction=0·77), but absolute risk reduction (aRR) increased with the number of metabolic risk factors (no risk factors aRR 0·7%, -1·81 to 3·29 vs five risk factors aRR 3·9%, -1·45 to 9·25; pinteraction<0·001). Similarly, when patients with diabetes were excluded, the incidence of MACE in the placebo group increased from 7·7% in patients with no metabolic risk factors to 14·6% in those with five metabolic risk factors and aRR with alirocumab increased from 0·91% in patients with no metabolic risk factors to 3·82% in those with five factors. Alirocumab was well tolerated in all subgroups defined by the presence of metabolic risk factors. INTERPRETATION: Accumulation of metabolic risk factors was associated with higher risk of MACE in patients with recent acute coronary syndrome. Alirocumab reduced MACE consistently, but aRR increased with number of metabolic risk factors. FUNDING: Sanofi and Regeneron Pharmaceuticals.

Nuclear medicine imaging methods of radiation-induced cardiotoxicity.

Breast cancer survival is significantly improved over the past decades due to major improvements in anti-tumor therapies and the implementation of regular screening, which leads to early detection of breast cancer. Therefore, it is of utmost importance to prevent patients from long-term side effects, including radiotherapy-induced cardiotoxicity. Radiotherapy may contribute to damage of myocardial structures on the cellular level, which eventually could result in various types of cardiovascular problems, including coronary artery disease and (non-)ischemic cardiomyopathy, leading to heart failure. These cardiac complications of radiotherapy are preceded by alterations in myocardial perfusion and blood flow. Therefore, early detection of these alterations is important to prevent the progression of these pathophysiological processes. Several radionuclide imaging techniques may contribute to the early detection of these changes. Single-Photon Emission Computed Tomography (SPECT) cameras can be used to create Multigated Acquisition scans in order to assess the left ventricular systolic and diastolic function. Furthermore, SPECT cameras are used for myocardial perfusion imaging with radiopharmaceuticals such as 99mTc-sestamibi and 99mTc-tetrofosmin. Accurate quantitative measurement of myocardial blood flow (MBF), can be performed by Positron Emission Tomography (PET), as the uptake of some of the tracers used for PET-based MBF measurement almost creates a linear relationship with MBF, resulting in very accurate blood flow quantification. Furthermore, there are PET and SPECT tracers that can assess inflammation and denervation of the cardiac sympathetic nervous system. Research over the past decades has mainly focused on the long-term development of left ventricular impairment and perfusion defects. Considering laterality of the breast cancer, some early studies have shown that women irradiated for left-sided breast cancer are more prone to cardiotoxic side effects than women irradiated for right-sided breast cancer. The left-sided radiation field in these trials, which predominantly used older radiotherapy techniques without heart-sparing techniques, included a larger volume of the heart and left ventricle, leading to increased unavoidable radiation exposure to the heart due to the close proximity of the radiation treatment volume. Although radiotherapy for breast cancer exposes the heart to incidental radiation, several improvements and technical developments over the last decades resulted in continuous reduction of radiation dose and volume exposure to the heart. In addition, radiotherapy reduces loco-regional tumor recurrences and death from breast cancer and improves survival. Therefore, in the majority of patients, the benefits of radiotherapy outweigh the potential very low risk of cardiovascular adverse events after radiotherapy. This review addresses existing nuclear imaging techniques, which can be used to evaluate (long-term) effects of radiotherapy-induced mechanical cardiac dysfunction and discusses the potential use of more novel nuclear imaging techniques, which are promising in the assessment of early signs of cardiac dysfunction in selected irradiated breast cancer patients.

Alirocumab after acute coronary syndrome in patients with a history of heart failure.

AIMS: Patients with heart failure (HF) have not been shown to benefit from statins. In a post hoc analysis, we evaluated outcomes in ODYSSEY OUTCOMES in patients with vs. without a history of HF randomized to the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab or placebo. METHODS AND RESULTS: Among 18 924 patients with recent acute coronary syndrome (ACS) receiving intensive or maximum-tolerated statin treatment, the primary outcome of major adverse cardiovascular events (MACE) was compared in patients with or without a history of HF. The pre-specified secondary outcome of hospitalization for HF was also analysed. Overall, 2815 (14.9%) patients had a history of HF. Alirocumab reduced low-density lipoprotein cholesterol and lipoprotein(a) similarly in patients with or without HF. Overall, alirocumab reduced MACE compared with placebo [hazard ratio (HR): 0.85; 95% confidence interval (CI): 0.78-0.93; P = 0.0001]. This effect was observed among patients without a history of HF (HR: 0.78; 95% CI: 0.70-0.86; P < 0.0001), but not in those with a history of HF (HR: 1.17; 95% CI: 0.97-1.40; P = 0.10) (Pinteraction = 0.0001). Alirocumab did not reduce hospitalization for HF, overall or in patients with or without prior HF. CONCLUSION: Alirocumab reduced MACE in patients without a history of HF but not in patients with a history of HF. Alirocumab did not reduce hospitalizations for HF in either group. Patients with a history of HF are a high-risk group that does not appear to benefit from PCSK9 inhibition after ACS.

Evaluation of High Cholesterol and Risk of Dementia and Cognitive Decline in Older Adults Using Individual Patient Meta-Analysis.

INTRODUCTION: Although increased cholesterol level has been acknowledged as a risk factor for dementia, evidence synthesis based on published data has yielded mixed results. This is especially relevant in older adults where individual studies report non-linear relationships between cholesterol and cognition and, in some cases, find higher cholesterol associated with a lower risk of subsequent cognitive decline or dementia. Prior evidence synthesis based on published results has not allowed us to focus on older adults or to standardize analyses across studies. Given our ageing population, an increased risk of dementia in older adults, and the need for proportionate treatment in this age group, an individual participant data (IPD) meta-analysis is timely. METHOD: We combined data from 8 studies and over 21,000 participants aged 60 years and over in a 2-stage IPD to examine the relationship between total, high-density, and low-density lipoprotein (HDL and LDL) cholesterol and subsequent incident dementia or cognitive decline, with the latter categorized using a reliable change index method. RESULTS: Meta-analyses found no relationship between total, HDL, or LDL cholesterol (per millimoles per litre increase) and risk of cognitive decline in this older adult group averaging 76 years of age. For total cholesterol and cognitive decline: odds ratio (OR) 0.93 (95% confidence interval [CI] 0.86: 1.01) and for incident dementia: OR 1.01 [95% CI 0.89: 1.13]. This was not altered by rerunning the analyses separately for statin users and non-users or by the presence of an APOE e4 allele. CONCLUSION: There were no clear consistent relationships between cholesterol and cognitive decline or dementia in this older adult group, nor was there evidence of effect modification by statin use. Further work is needed in younger populations to understand the role of cholesterol across the life-course and to identify any relevant intervention points. This is especially important if modification of cholesterol is to be further evaluated for its potential influence on risk of cognitive decline or dementia.

Common Genetic Variation in MC4R Does Not Affect Atherosclerotic Plaque Phenotypes and Cardiovascular Disease Outcomes.

We analyzed the effects of the common BMI-increasing melanocortin 4 receptor (MC4R) rs17782313-C allele with a minor allele frequency of 0.22-0.25 on (1) cardiovascular disease outcomes in two large population-based cohorts (Copenhagen City Heart Study and Copenhagen General Population Study, n = 106,018; and UK Biobank, n = 357,426) and additionally in an elderly population at risk for cardiovascular disease (n = 5241), and on (2) atherosclerotic plaque phenotypes in samples of patients who underwent endarterectomy (n = 1439). Using regression models, we additionally analyzed whether potential associations were modified by sex or explained by changes in body mass index. We confirmed the BMI-increasing effects of +0.22 kg/m2 per additional copy of the C allele (p < 0.001). However, we found no evidence for an association of common MC4R genetic variation with coronary artery disease (HR 1.03; 95% CI 0.99, 1.07), ischemic vascular disease (HR 1.00; 95% CI 0.98, 1.03), myocardial infarction (HR 1.01; 95% CI 0.94, 1.08 and 1.02; 0.98, 1.07) or stroke (HR 0.93; 95% CI 0.85, 1.01), nor with any atherosclerotic plaque phenotype. Thus, common MC4R genetic variation, despite increasing BMI, does not affect cardiovascular disease risk in the general population or in populations at risk for cardiovascular disease.

Comparison of P2Y12 receptor inhibitors in patients with ST-elevation myocardial infarction in clinical practice: a propensity score analysis of five contemporary European registries.

AIMS: Among acute coronary syndromes (ACS), ST-segment elevation myocardial infarction (STEMI) has the most severe early clinical course. Recent randomized clinical trials have demonstrated that novel antithrombotic therapies improve in-hospital outcomes in STEMI patients. We aimed to describe the effectiveness and safety of P2Y12 receptor inhibitors in clinical practice in patients with STEMI based on data from contemporary European ACS registries. METHODS AND RESULTS: Five registries from the PIRAEUS initiative (AAPCI/ADPAT, ALKK-PIC, AMIS Plus, Belgium STEMI, and EYESHOT) provided data for the assessment of P2Y12 receptor inhibitor-based dual antiplatelet therapy. Registries were heterogeneous in terms of setting, patient characteristics, and treatment selection. Matched pair analysis and propensity score matching were used to assess all-cause in-hospital death rates based on data from 25 250 patients (8577 patients on prasugrel, 5995 on ticagrelor, and 10 678 on clopidogrel). The odds ratio (OR) for the death of any cause when compared with clopidogrel was 0.72 [95% confidence interval (CI) 0.62-0.84, P < 0.001] in favour of the new P2Y12 receptor inhibitors (prasugrel and ticagrelor combined). In the comparison between prasugrel and ticagrelor, there were no relevant differences (OR 0.97, 95% CI 0.77-1.23; P = 0.81). Event rates of cardiovascular death and stroke were also substantially lower for the new P2Y12 receptor inhibitors. The differences between clopidogrel and prasugrel or ticagrelor on major bleeding were numerically in the same order as for death of any cause but were not statistically significant. No differences in ischaemic and bleeding outcomes were observed between prasugrel and ticagrelor. CONCLUSION: This analysis suggests that the prasugrel or ticagrelor compared with clopidogrel have favourable outcomes in clinical practice while not being inferior in terms of safety.

Visit-to-visit lipid variability: Clinical significance, effects of lipid-lowering treatment, and (pharmaco) genetics.

In recent years, visit-to-visit variability of serum lipids has been linked to both clinical outcomes and surrogate markers for vascular disease. In this article, we present an overview of the current evidence connecting this intraindividual variability to these outcome measures, discuss its interplay with lipid-lowering treatment, and describe the literature regarding genetic factors of possible interest. In addition, we undertook an explorative genome-wide association analysis on visit-to-visit variability of low-density lipoprotein cholesterol and high-density lipoprotein cholesterol, examining additive effects in 2530 participants from the placebo arm of the PROspective Study of Pravastatin in the Elderly at Risk trial. While we identified suggestive associations (P < 1 × 10-6) at 3 different loci (KIAA0391, amiloride-sensitive cation channel 1 neuronal [ACCN1], and Dickkopf WNT signaling pathway inhibitor 3 [DKK3]), previously published data from the genome-wide association study literature did not suggest plausible mechanistic pathways. Given the large degree of both clinical and methodological heterogeneity in the literature, additional research is needed to harmonize visit-to-visit variability parameters across studies and to definitively assess the possible role of (pharmaco)genetic factors.

Scarcity of atrial fibrillation in a traditional African population: a community-based study.

BACKGROUND: In western societies, atrial fibrillation is an increasingly common finding among the elderly. Established risk factors of atrial fibrillation include obesity, diabetes, hypertension, and cardiovascular disease. Atrial fibrillation has almost exclusively been studied in western populations where these risk factors are widely present. Therefore, we studied the epidemiology of atrial fibrillation in a traditional African community. METHODS: In rural Ghana, among 924 individuals aged 50 years and older, we recorded electrocardiograms to detect atrial fibrillation. As established risk factors, we documented waist circumference, body mass index (BMI), capillary glucose level, blood pressure, and electrocardiographic myocardial infarction. In addition, we determined circulating levels of interleukin-6 (IL6), a proinflammatory cytokine, and C-reactive protein (CRP), a marker of systemic inflammation. We compared the risk factors with reference data from the USA. RESULTS: Atrial fibrillation was detected in only three cases, equalling 0.3% (95% CI 0.1-1.0%). Waist circumference, BMI, and capillary glucose levels were very low. Hypertension and myocardial infarction were uncommon. Circulating levels of IL6 were similar, but those of CRP were lower compared with the USA. CONCLUSION: Atrial fibrillation is very scarce in this traditional African community. Its low prevalence compared with western societies can be explained by the rareness of its established risk factors, which are closely related to lifestyle, and by possible unmeasured differences in other risk factors or genetic factors.

The Netherlands Epidemiology of Obesity (NEO) study: study design and data collection.

Obesity is a well-established risk factor for many chronic diseases. Incomplete insight exists in the causal pathways responsible for obesity-related disorders and consequently, in the identification of obese individuals at risk of these disorders. The Netherlands Epidemiology of Obesity (NEO) study is designed for extensive phenotyping to investigate pathways that lead to obesity-related diseases. The NEO study is a population-based, prospective cohort study that includes 6,673 individuals aged 45-65 years, with an oversampling of individuals with overweight or obesity. At baseline, data on demography, lifestyle, and medical history have been collected by questionnaires. In addition, samples of 24-h urine, fasting and postprandial blood plasma and serum, and DNA were collected. Participants underwent an extensive physical examination, including anthropometry, electrocardiography, spirometry, and measurement of the carotid artery intima-media thickness by ultrasonography. In random subsamples of participants, magnetic resonance imaging of abdominal fat, pulse wave velocity of the aorta, heart, and brain, magnetic resonance spectroscopy of the liver, indirect calorimetry, dual-energy X-ray absorptiometry, or accelerometry measurements were performed. The collection of data started in September 2008 and completed at the end of September 2012. Participants are followed for the incidence of obesity-related diseases and mortality. The NEO study investigates pathways that lead to obesity-related diseases. A better understanding of the mechanisms underlying the development of disease in obesity may help to identify individuals who are susceptible to the detrimental metabolic, cardiovascular and other consequences of obesity and has implications for the development of prevention and treatment strategies.