Thomas D. Gossios

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.

Role of Antihypertensive Drugs in Arterial 'De-Stiffening' and Central Pulsatile Hemodynamics

Arterial stiffness is an independent predictor of cardiovascular (CV) morbidity and mortality in patients with hypertension, as well as a potential therapeutic target. There is increasing awareness that the pulsatile hemodynamics (central blood pressure [CBP], pulse pressure [PP], wave reflections [augmentation index or AIx] and pulse wave velocity [PWV]) may provide better insight into the pathophysiology of CV disorders and target organ damage related to hypertension. Different antihypertensive drugs produce diverse effects on arterial stiffness variables, despite similar effects on peripheral (brachial) blood pressure. Identifying the pharmacologic interventions that can improve arterial stiffness (‘de-stiffening’ treatment) is a promising field of research.

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.

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 Effect of Antihypertensive Agents on Insulin Sensitivity, Lipids and Haemostasis

Antihypertensive agents exert different effects on insulin sensitivity, lipids and haemostasis. However, most studies assessing these effects were small and short-term yielding conflicting results. Moreover, it has not been established whether the impact of antihypertensive drugs on insulin sensitivity, lipids, thrombosis and fibrinolysis adds to or attenuates vascular risk reduction. On the other hand, new onset type 2 diabetes mellitus (T2DM) appears to be more frequent in patients treated with β-blockers and diuretics, whereas angiotensin converting enzyme inhibitors and angiotensin receptor blockers might reduce the risk for T2DM and calcium channel blockers have a neutral effect. Therefore, the risk of developing T2DM should be considered when selecting an antihypertensive agent. This review discusses the differential effects of antihypertensive drugs on insulin sensitivity, lipids and haemostasis and considers their association with vascular risk.

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.

Is there an additional benefit from coronary revascularization in diabetic patients with acute coronary syndromes or stable angina who are already on optimal medical treatment

Cardiovascular disease (CVD) is common in patients with diabetes mellitus (DM) and related clinical outcomes are worse compared with non-diabetics. The optimal treatment in diabetic patients with coronary heart disease (CHD) is currently not established. We searched MEDLINE (1975-2010) using the key terms diabetes mellitus, coronary heart disease, revascularization, coronary artery bypass, angioplasty, coronary intervention and medical treatment. Most studies comparing different revascularization procedures in patients with CHD favoured coronary artery bypass graft (CABG) surgery in patients with DM. However, most of this evidence comes from subgroup analyses. Recent evidence suggests that advanced percutaneous coronary intervention (PCI) techniques along with best medical treatment may be non-inferior and more cost-effective compared with CABG. Treatment of vascular risk factors is a key option in terms of improving CVD outcomes in diabetic patients with CHD. The choice between medical therapy and revascularization warrants further assessment.

Treating Heart Failure with Preserved Ejection Fraction Related to Arterial Stiffness. Can we Kill Two Birds With One Stone

Heart failure with preserved ejection fraction (HFpEF). Arterial hypertension (AH), arterial stiffness (AS), older age, and female gender are the main determinants of HFpEF, but several cardiac or extra-cardiac pathologies are also possible causes. The combined ventricular-vascular stiffening (abnormal left atrium-left ventricle coupling related to AS) is the main contributor of the increased prevalence of HFpEF in elderly persons, particularly elderly women, and in younger persons with AH. The hospitalization and mortality rates of HFpEF are similar to those of heart failure with reduced EF (HFrEF). However, although the prognosis of HFrEF has been substantially improved during the last 2 decades, the effective treatment of HFpEF remains an unmet need. Regimens effective in HFrEF have no substantial effect on HFpEF, because of different pathophysiologies of the 2 syndromes. Pipeline drugs seem promising, but it will take some years before they are commercially available. Aggressive treatment of noncardiac comorbidities seems to be the only option at hand. Treatment of anaemia, sleep disorders, chronic kidney disease (CKD), non-alcoholic fatty liver (NAFLD), atrial fibrillation, diabetes, and careful use of diuretics to reduce preload are effective to some degree. Statin treatment, despite the presence of dyslipidaemia, deserves special attention because it has been proven, mainly in small studies or post hoc analyses of trials, that it offers a substantial improvement in quality of life and a reduction in mortality rates. We need to urgently utilize these recourses to relieve a considerable part of the general population suffering from HFpEF, a deadly disease.