Eleni Theocharidou

Safety and efficacy of long-term statin treatment for cardiovascular events in patients with coronary heart disease and abnormal liver tests in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study: a post-hoc analysis

BACKGROUND Long-term statin treatment reduces the frequency of cardiovascular events, but safety and efficacy in patients with abnormal liver tests is unclear. We assessed whether statin therapy is safe and effective for these patients through post-hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study population. METHODS GREACE was a prospective, intention-to-treat study that randomly assigned by a computer-generated randomisation list 1600 patients with coronary heart disease (aged <75 years, with serum concentrations of LDL cholesterol >2·6 mmol/L and triglycerides <4·5 mmol/L) at the Hippokration University Hospital, Thessaloniki, Greece to receive statin or usual care, which could include statins. The primary outcome of our post-hoc analysis was risk reduction for first recurrent cardiovascular event in patients treated with a statin who had moderately abnormal liver tests (defined as serum alanine aminotransferase or aspartate aminotransferase concentrations of less than three times the upper limit of normal) compared with patients with abnormal liver tests who did not receive a statin. This risk reduction was compared with that for patients treated (or not) with statin and normal liver tests. FINDINGS Of 437 patients with moderately abnormal liver tests at baseline, which were possibly associated with non-alcoholic fatty liver disease, 227 who were treated with a statin (mainly atorvastatin 24 mg per day) had substantial improvement in liver tests (p<0·0001) whereas 210 not treated with a statin had further increases of liver enzyme concentrations. Cardiovascular events occurred in 22 (10%) of 227 patients with abnormal liver tests who received statin (3·2 events per 100 patient-years) and 63 (30%) of 210 patients with abnormal liver tests who did not receive statin (10·0 events per 100 patient-years; 68% relative risk reduction, p<0·0001). This cardiovascular disease benefit was greater (p=0·0074) than it was in patients with normal liver tests (90 [14%] events in 653 patients receiving a statin [4·6 per 100 patient-years] vs 117 [23%] in 510 patients not receiving a statin [7·6 per 100 patient-years]; 39% relative risk reduction, p<0·0001). Seven (<1%) of 880 participants who received a statin discontinued statin treatment because of liver-related adverse effects (transaminase concentrations more than three-times the upper limit of normal). INTERPRETATION Statin treatment is safe and can improve liver tests and reduce cardiovascular morbidity in patients with mild-to-moderately abnormal liver tests that are potentially attributable to non-alcoholic fatty liver disease. FUNDING None.

Safety and impact on cardiovascular events of long-term multifactorial treatment in patients with metabolic syndrome and abnormal liver function tests: a post hoc analysis of the randomised ATTEMPT study

Introduction Non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of metabolic syndrome (MetS), is common and accounts for 80% of cases of elevated liver function tests (LFTs). We assessed the long-term effects of multifactorial intervention on LFTs and their association with cardiovascular disease (CVD) events in patients with MetS without diabetes mellitus or CVD. Material and methods This prospective, randomized, open label study included 1,123 patients (aged 45-65 years). Patients received intensive lifestyle intervention and pharmacotherapy: atorvastatin in all patients (low density lipoprotein cholesterol [LDL-C] targets of<100 mg/dl [group A] or<130 mg/dl [group B]), inhibitors of the renin-angiotensin-aldosterone axis for hypertension, metformin for dysglycaemia and orlistat for obesity. Results Among participants, 326 had modestly elevated LFTs and ultrasonographic (US) evidence of NAFLD (165 patients in group A2 and 161 patients in group B2). The NAFLD resolved during the 42-month treatment period in 86% of patients in group A2 and in 74% of patients in group B2 (p<0.001). In both groups nearly 90% of patients attained lipid goals. Mean LDL-C and TG levels were higher in group B2 than in group A2 (p<0.001). There were no CVD events in group A2 whereas 5 non-fatal events occurred in group B2 (log-rank-p = 0.024). There were no major side-effects. Conclusions Attaining multiple treatment targets is safe and beneficial in primary prevention patients with MetS and NAFLD. Lipid levels and LFTs normalized, US findings associated with NAFLD resolved and no CVD events occurred in patients with LDL-C levels<100 mg/dl (group A2). Resolution of NAFLD might have contributed to the prevention of CVD events.

The Royal Free Hospital Score: A Calibrated Prognostic Model for Patients With Cirrhosis Admitted to Intensive Care Unit. Comparison With Current Models and CLIF-SOFA Score

OBJECTIVES:Prognosis for patients with cirrhosis admitted to intensive care unit (ICU) is poor. ICU prognostic models are more accurate than liver-specific models. We identified predictors of mortality, developed a novel prognostic score (Royal Free Hospital (RFH) score), and tested it against established prognostic models and the yet unvalidated Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) model.METHODS:Predictors of mortality were defined by logistic regression in a cohort of 635 consecutive patients with cirrhosis admitted to ICU (1989–2012). The RFH score was derived using a 75% training and 25% validation set. Predictive accuracy and calibration were evaluated using area under the receiver operating characteristic (AUROC) and goodness-of-fit χ2 for the RFH score, as well as for SOFA, Model for End-Stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE II), and Child-Pugh. CLIF-SOFA was applied to a recent subset (2005–2012) of patients.RESULTS:In-hospital mortality was 52.3%. Mortality improved over time but with a corresponding reduction in acuity of illness on admission. Predictors of mortality in training set, which constituted the RFH score, were the following: bilirubin, international normalized ratio, lactate, alveolar arterial partial pressure oxygen gradient, urea, while variceal bleeding as indication for admission conferred lesser risk. Classification accuracy was 73.4% in training and 76.7% in validation sample and did not change significantly across different eras of admission. The AUROC for the derived model was 0.83 and the goodness-of-fit χ2 was 3.74 (P=0.88). AUROC for SOFA was 0.81, MELD was 0.79, APACHE II was 0.78, and Child-Pugh was 0.67. In 2005–2012 cohort, AUROC was: SOFA: 0.74, CLIF-SOFA: 0.75, and RFH: 0.78. Goodness-of-fit χ2 was: SOFA: 6.21 (P=0.63), CLIF-SOFA: 9.18 (P=0.33), and RFH: 2.91 (P=0.94).CONCLUSIONS:RFH score demonstrated good discriminative ability and calibration. Internal validation supports its generalizability. CLIF-SOFA did not perform better than RFH and the original SOFA. External validation of our model should be undertaken to confirm its clinical utility.

Statins and cardiovascular outcomes in elderly and younger patients with coronary artery disease: a post hoc analysis of the GREACE study

Introduction The effect of cardiovascular disease (CVD) prevention measures aimed at elderly patients requires further evidence. We investigated the effect of statin treatment (targeted to achieve guideline goals) on CVD outcomes in different age groups to determine whether statins are more beneficial in the elderly. Material and methods The primary endpoint of this post hoc analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study (n = 1,600 patients with established coronary heart disease (CHD), mean follow-up 3 years) was the absolute and relative CVD event (a composite of death, myocardial infarction, revascularization, unstable angina, heart failure and stroke) risk reduction in age quartiles (each n = 200). Patients on “structured care” with atorvastatin (n = 800) followed up by the university clinic and treated to lipid goal were compared with the corresponding quartiles on “usual care” (n = 800) followed up by specialists or general practitioners of the patients choice outside the hospital. Results In the elderly (mean age 69 ±4 and 70 ±3 years in the “structured” and “usual care”, respectively) the absolute CVD event reduction between “structured” and “usual care” was 16.5% (p < 0.0001), while in the younger patients (mean age 51 ±3 years and 52 ±3 years in the “structured” and “usual care”, respectively) this was 8.5% (p = 0.016); relative risk reduction (RRR) 60% (p < 0.0001) vs. 42% respectively (p = 0.001). The elderly had higher rates of chronic kidney disease and higher uric acid levels, plus an increased prevalence of diabetes, metabolic syndrome and non-alcoholic fatty liver disease. These factors might contribute to the increased CVD risk in older patients. Conclusions All age groups benefited from statin treatment, but the elderly on “structured care” had a greater absolute and relative CVD risk reduction than the younger patients when compared with the corresponding patients assigned to “usual care”. These findings suggest that we should not deprive older patients of CVD prevention treatment and lipid target achievement.

Ezetimibe Therapy for Dyslipidemia: An Update

Ezetimibe, an inhibitor of intestinal cholesterol absorption, can decrease total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglycerides (TGs) and apolipoprotein (apo) B levels and increase high-density lipoprotein cholesterol (HDL-C) levels. Apart from lipid-lowering, ezetimibe may exert certain off-target actions (e.g. anti-inflammatory, anti-atherogenic and antioxidant) thus contributing to a further decrease of cardiovascular disease (CVD) risk.Ezetimibe trials resulted in controversial outcomes with some studies reporting atherosclerosis regression and reductions in CVD events following ezetimibe therapy in combination with a statin while others reported negative results. The results of the ongoing IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT) which compares ezetimibe plus simvastatin with simvastatin monotherapy with regard to CVD outcomes after acute coronary syndromes should further elucidate the effect of ezetimibe on CVD events.This review presents the results of up-to-date clinical trials with ezetimibe and summarizes its potential pleiotropic effects. Furthermore, we comment on the administration of ezetimibe in treating high-risk patients [i.e. with diabetes mellitus (DM), metabolic syndrome (MetS), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease (CKD), peripheral artery disease (PAD) or carotid disease]. The use of ezetimibe either as monotherapy or as add-on therapy in daily clinical practice is also discussed.

Carotid intima-media thickness in patients with inflammatory bowel disease: a systematic review.

We systematically reviewed the available data on carotid intima-media thickness (cIMT) in patients with inflammatory bowel diseases (IBDs) without history of cardiovascular disease (CVD) and its associated factors. A total of 6 studies met the inclusion criteria including 217 patients with Crohns disease (CD) and 85 with ulcerative colitis (UC). Two studies included only patients with CD. The prevalence of traditional CVD risk factors and the inflammatory burden (IBD duration and activity) varied greatly among patients and studies. Factors that correlated with cIMT were age, male gender, body mass index, arterial hypertension, as well as cholesterol and homocysteine levels. The current data on cIMT in patients with IBD are inconclusive. This is probably due to small number of patients, population heterogeneity with regard to inflammatory burden and smoking habits, and lack of strict matching with controls. In order to elucidate any potential association between IBD and CVD risk, larger prospective studies are required.

Lipoprotein-associated phospholipase A2 and arterial stiffness evaluation in patients with inflammatory bowel diseases

BACKGROUND AND AIMS The association between inflammatory bowel diseases (IBD) and cardiovascular disease (CVD) remains equivocal. Arterial stiffness, as assessed by pulse wave velocity (PWV), and lipoprotein-associated phospholipase A2 (Lp-PLA2) are surrogates of CVD risk. AIM The aim of this study was to assess carotid-femoral PWV and Lp-PLA2 in patients with IBD without history of CVD. METHODS Established CVD risk factors, IBD characteristics, PWV and Lp-PLA2 activity were assessed in 44 patients with IBD, 29 with Crohns disease (CD) and 15 with ulcerative colitis (UC), and 44 matched controls. RESULTS IBD patients had lower total and low density lipoprotein cholesterol (LDL-C) levels. There was no difference in PWV between patients and controls (6.8 vs. 6.4m/s), but patients with CD had higher PWV compared to those with UC (7 vs. 6.3m/s; p=0.044), and to controls. Smoking rates were significantly higher among CD patients. Factors associated with PWV were age, mean arterial pressure and smoking. Lp-PLA2 activity was significantly lower in patients with IBD (46.8 vs. 53.9 nmol/mL/min; p=0.011). There was no difference in Lp-PLA2 between CD and UC patients. LDL-C was the only significant predictor of Lp-PLA2. CONCLUSIONS Our study showed lower Lp-PLA2 activity in patients with IBD compared with controls, reflecting lower LDL-C in the former. There was no difference in PWV between the two groups. Arterial stiffness was higher in patients with CD, which is likely related to higher smoking rates. These findings challenge a possible association between IBD and CVD, but further studies are required.

Is There an Association Between Inflammatory Bowel Diseases and Carotid Intima-media Thickness? Preliminary Data

Inflammation is a predictor of cardiovascular disease (CVD). Thus, inflammatory bowel diseases (IBD) may be associated with CVD. We assessed carotid intima-media thickness (cIMT; an indicator of CVD risk) in 42 patients with IBD, free of CVD or diabetes; 26 with Crohns disease (CD) and 16 with ulcerative colitis (UC). The cIMT was significantly greater in patients with IBD compared to 42 healthy controls (0.62 ± 0.08 vs 0.52 ± 0.06 mm; P < .0005). The cIMT did not differ between patients with CD and UC or between the different disease activity and treatment groups. Factors associated with cIMT were age, body mass index, and IBD, with the latter making a greater contribution. The IBD is a predictor of cIMT, even when other CVD risk factors are considered. These findings suggest an association between early arterial wall alterations and IBD. Such an association should be proven in larger studies that should assess the incidence of CVD in patients with IBD.

The impact of smoking on cardiovascular outcomes and comorbidities in statin-treated patients with coronary artery disease: a post hoc analysis of the GREACE study.

BACKGROUND Smoking adversely affects cardiovascular disease (CVD) morbidity and mortality; however the effect of long-term statin treatment in high risk smokers is not entirely clear. The primary endpoint of this post hoc analysis of the GREek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study (n=1,600 patients with established coronary heart disease, mean follow-up 3-years) was the incidence of major CVD events, a composite of death, myocardial infarction, revascularization, unstable angina, heart failure, and stroke in statin-treated patients (n=880) who continued to smoke (n=129) compared with ex-smokers (n=309) and never smokers (n=442) as well as on patients not treated with a statin (n=720) of all smoking categories. Secondary endpoints were the effect of smoking on chronic kidney disease (CKD) and on non-alcoholic fatty liver disease (NAFLD), two major and common independent CVD risk factors. RESULTS Among statin treated patients the hazard ratio (HR) for current smokers compared with never smokers was 1.86 [95% confidence interval-(CI) 1.19-2.10); similar was the HR for current smokers compared with ex-smokers. Absolute (16.3%) and relative (45.6%) CVD risk reduction was great in current smokers on statins compared with those not on a statin; however they still had the highest absolute CVD event incidence (19.4%). Low high density lipoprotein cholesterol and higher triglycerides may account, at least in part, for this. The highest risk of CVD events in any of the 6 groups was in the smokers not on a statin (35.7%). CKD and NAFLD were not negatively affected by smoking and they do not appear to be implicated in the adverse effect of smoking on CVD event rate in patients on a statin. CONCLUSIONS Statins reduce CVD morbidity and mortality in current smokers with CVD, but these remain high in terms of absolute incidence compared with ex- and never smokers. CKD and NAFLD are not affected by smoking and do not seem to contribute to this high CVD event incidence. These make smoking cessation imperative in high risk patients even if they are on statins.

Development and validation of a mathematical equation to estimate glomerular filtration rate in cirrhosis: The royal free hospital cirrhosis glomerular filtration rate.

Current expressions based on serum creatinine concentration overestimate kidney function in cirrhosis, leading to significant differences between “true” and calculated glomerular filtration rate (GFR). We compared the performance of the four‐variable and six‐variable Modification of Diet in Renal Disease and chronic kidney disease epidemiology with “true,” or measured, GFR (mGFR) and the impact of this difference on Model for End‐Stage Liver Disease (MELD) calculation. We subsequently developed and validated a GFR equation specifically for cirrhosis and compared the performance of the new derived formula with existing GFR formulae. We included 469 consecutive patients who had a transplant assessment between 2011 and 2014. mGFR was measured using plasma isotope clearance according to a technique validated in patients with ascites. A corrected creatinine was derived from the mGFR after application of the Modification of Diet in Renal Disease formula. Subsequently, a corrected MELD was calculated and compared with the conventionally calculated MELD. Stepwise multiple linear regression was used to derive a GFR equation. This was compared with the mGFR in independent external and internal validation sets of 82 and 174 patients with cirrhosis, respectively. A difference >20 mL/minute/1.73 m2 between existing formulae and mGFR was observed in 226 (48.2%) patients. The corrected MELD score was ≥3 points higher in 177 (37.7%) patients. The predicted equation (r2 = 74.6%) was GFR = 45.9 × (creatinine–0·836) × (urea–0·229) × (international normalized ratio–0·113) × (age−0.129 [Corrected November 29, 2016: originally written as “age‐129.”]) × (sodium0·972) × 0.809 (if female) × 0.92 (if moderate/severe ascites). An online calculator is available at http://rfh-cirrhosis-gfr.ucl.ac.uk. The model was a good fit and showed the greatest accuracy compared to that of existing formulae. Conclusion: We developed and validated a new accurate model for GFR assessment in cirrhosis, the Royal Free Hospital cirrhosis GFR, using readily available variables; this remains to be tested and incorporated in prognostic scores in patients with cirrhosis. (Hepatology 2017;65:582‐591).