Athanasios A. Papageorgiou

The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. A subgroup analysis of the Greek atorvastatin and coronary heart disease evaluation (GREACE) study

Background: Little is known about statins in the prevention of dyslipidaemia induced renal function decline. The secondary coronary heart disease (CHD) prevention GREACE study suggested that dose titration with atorvastatin (10–80 mg/day, mean dose 24 mg/day) achieves the national cholesterol educational programme treatment goals and significantly reduces morbidity and mortality, compared with usual care. Aims: To report the effect of statin on renal function compared with untreated dyslipidaemia in both treatment groups. Methods/Results: All patients had plasma creatinine values within the reference range < 115 µmol/litre (13 mg/litre). The on study creatinine clearance (CrCl), as estimated (for up to 48 months) by the Cockroft-Gault formula, was compared within and between treatment groups using analysis of variance to assess differences over time. Patients from both groups not treated with statins (704) showed a 5.2% decrease in CrCl (p < 0.0001). Usual care patients on various statins (97) had a 4.9% increase in CrCl (p  =  0.003). Structured care patients on atorvastatin (783) had a 12% increase in CrCl (p < 0.0001). This effect was more prominent in the lower two quartiles of baseline CrCl and with higher atorvastatin doses. After adjustment for 25 predictors of all CHD related events, multivariate analysis revealed a hazards ratio of 0.84 (confidence interval 0.73 to 0.95; p  =  0.003) with every 5% increase in CrCl. Conclusions: In untreated dyslipidaemic patients with CHD and normal renal function at baseline, CrCl declines over a period of three years. Statin treatment prevents this decline and significantly improves renal function, potentially offsetting an additional factor associated with CHD risk.

Safety and Efficacy of Long-Term Statin- Fibrate Combinations in Patients With Refractory Familial Combined Hyperlipidemia

No monotherapy is able to tackle effectively all atherogenic features of familial combined hyperlipidemia: high low-density lipoprotein (LDL) cholesterol, triglycerides (TG), and plasma fibrinogen, as well as low high-density lipoprotein (HDL) cholesterol. The present study investigated the safety and efficacy of combined pravastotin or simvastatin with gemfibrozil or ciprofibrate treatment on total cholesterol, LDL, TG, plasma fibrinogen, and apoproteins B and A-I in patients with refractory familial combined hyperlipidemia, with or without coronary artery disease. From the initial 420 patients included in the study, 389 (294 men and 95 women, mean age 51 years [range 30 to 65]) completed the study. These patients were followed for a mean period of 29 months (1 year [n = 107], 2 years [n = 102], 3 years [n = 95], and 4 years [n = 85]). Patients given a hypolipidemic diet were randomly assigned to pravastatin + gemfibrozil (n = 135, 20 and 1,200 mg/day, respectively), simvastatin + gemfibrozil (n = 130, 20 and 1,200 mg), or simvastotin + ciprofibrate (n = 124, 20 and 100 mg). Lipid parameters, apoproteins B and A-I, and plasma fibrinogen were assessed every 3 months. Physical and laboratory investigations for adverse effects were performed every month for the first 3 months and every 3 months thereafter. No patient exhibited myopathy or rhabdomyolysis. Five patients (1.3%) were withdrawn from the study because of high transaminases (more than threefold the upper normal limit). Five nonfatal coronary artery disease events were recorded. All 3 combination treatments were more effective in normalizing lipid profile than any monotherapy in the past. Simvastatin + ciprofibrate was more effective than pravastatin + gemfibrozil in reducing LDL, TG, and plasma fibrinogen levels. Simvastatin + gemfibrozil increased HDL levels more than the other 2. The apoprotein B decrease was analogous to the LDL reduction by all combinations, whereas apoprotein A-I was increased more with simvastatin + gemfibrozil. The data suggest that the statin-fibrate combinations used in the study are safe and have a favorable effect on all major coronary artery disease risk factors in patients with refractory familial combined hyperlipidemia with or without coronary artery disease. Early detection of the rare drug-induced reversible hepatotoxicity calls for close monitoring of patients.

The prevalence of the metabolic syndrome in Greece : The Mets-Greece Multicentre Study

Background:  The Third Report (ATP III) of the National Cholesterol Education Program Expert Panel (NCEP) highlighted the importance of identifying and treating patients with the metabolic syndrome (MetS) to prevent cardiovascular disease (CVD) and progression to diabetes mellitus. Limited information is available about the prevalence of MetS, as defined by the NCEP ATP III, in Europe, especially in Greece.

Association of Drinking Pattern and Alcohol Beverage Type With the Prevalence of Metabolic Syndrome, Diabetes, Coronary Heart Disease, Stroke, and Peripheral Arterial Disease in a Mediterranean Cohort

The purpose of this study was to investigate the relationship between alcohol consumption and the prevalence of the metabolic syndrome (MetS), type 2 diabetes mellitus (DM), coronary heart disease (CHD), stroke, peripheral arterial disease (PAD), and overall cardiovascular disease (CVD) in a Mediterranean cohort. It consisted of a cross-sectional analysis of a representative sample of Greek adults (n = 4153) classified as never, occasional, mild, moderate, or heavy drinkers. Cases with overt CHD, stroke, or PAD were recorded. In our population, 17% were never, 23% occasional, 27% mild, 24% moderate, and 9% heavy drinkers. Moderate alcohol consumption was associated with a lower trend for the prevalence of the MetS (P = .0001), DM (P < .0001), CHD (P = .0002), PAD (P = .005), and overall CVD (P = .001) but not stroke compared with no alcohol use. Heavy drinking was associated with an increase in the prevalence of all of these disease states. Wine consumption was associated with a slightly better effect than beer or spirits consumption on the prevalence of total CVD, and beer consumption was associated with a better effect than spirits consumption. Alcohol intake was positively related with body weight, high-density lipoprotein cholesterol levels, and hypertension. Moderate alcohol consumption is associated with a lower prevalence of the MetS, DM, PAD, CHD, and overall CVD but not stroke compared with no alcohol use in a Mediterranean population. Heavy drinking was associated with an increase in the prevalence of all of these disease states. Advice on alcohol consumption should probably mainly aim at reducing heavy drinking.

Effect of Chronic Quinapril Administration on Heart Rate Variability in Patients With Diabetic Autonomic Neuropathy

OBJECTIVE Heart rate variability (HRV) time and frequency domain indexes are strong predictors of malignant arrhythmias and sudden cardiac death. Patients with diabetic autonomic neuropathy (DAN) have an increased cardiovascular mortality rate compared with diabetic patients without DAN. RESEARCH DESIGN AND METHODS The present double-blind, randomized, and placebo-controlled study analyzed the effect of quinapril, an ACE inhibitor, on HRV time and frequency domain variables in patients with DAN. Forty patients (17 men and 23 women) of a mean age of 51 (range 19–68) years, free of coronary artery disease and arterial hypertension, were randomized into a quinapril or placebo group. HRV was recorded at months 0, 3, and 6. The parameters measured were 1) time domain indexes: SD of all 24-h R-R intervals (intervals between consecutive electrocardiogram R waves), or SDNN/24-h; mean of SD of R-R intervals of all 5-min segements (SDNN/5-min); root-mean-square of the differences of successive R-R intervals (RMSSD); and percentage of the R-R intervals differing more than 50 ms (pNN50); and 2) frequency domain indexes: total power (TP), high-frequency power (HFP), low-frequency power (LFP), and very-low-frequency power (VLFP). HRV level of the 40 patients were compared with one of 20 matched diabetic patients, of analogous glycemic control without DAN, and 20 healthy control subjects. RESULTS Quinapril, compared with placebo, increased total HRV: SDNN/24-h (P < 0.05), TP (P < 0.05), and HRV parameters related to parasympathetic activity: pNN50 (P < 0.01). RMSSD (P < 0.05), and HFP in absolute and normalized units (P < 0.01). LFP/HFP ratio was decreased (P < 0.01). Despite the beneficial effect of quinapril on parasympathetic variables of HRV these remained < those of diabetic patients without DAN and healthy control subjects. CONCLUSIONS Our findings suggest that quinapril significantly increases parasympathetic activity in patients with DAN 3 months after treatment initiation and sustains this effect until the 6th month. This might contribute to the reduction of the risk for malignant ventricular arrhythmias in these patients.

Heart rate variability after long-term treatment with atorvastatin in hypercholesterolaemic patients with or without coronary artery disease

Low heart rate variability (HRV) level, indicative of impaired autonomic function, is associated with an increased risk of cardiovascular morbidity and mortality and is negatively affected by hypercholesterolaemia. In order to test the hypothesis that significant low density lipoprotein (LDL) cholesterol reduction after treatment with a statin will have a beneficial effect on HRV level in hypercholesterolaemic patients with or without coronary artery disease (CAD), forty consecutive patients (28 men and 12 women) with a median age of 61, range (17--70) years were studied. Twenty had stable CAD and 20 were free of CAD at baseline. Twenty healthy volunteers, of similar age and gender as the patients, were used as controls. Patients were treated with atorvastatin (20 mg/day) for 2 years. Changes in lipid parameters and HRV indices were assessed at baseline and 2 years later in all subjects. In both patient subgroups a significant beneficial change in all lipid parameters (more pronounced in the CAD+ subgroup) and a significant beneficial modification in HRV time and frequency domain indices was recorded (more pronounced in the CAD- subgroup), while lipid parameters and HRV indices remained unchanged in the control group. A correlation between LDL concentrations and most of the HRV indices was found at baseline in both patient subgroups, while no such correlation was found between values or their percent changes after hypolipidaemic treatment. These data suggest that treatment with atorvastatin improves autonomic function, as reflected by an increase in HRV level, and this may be a likely mechanism, at least in part, for the reduction in clinical events reported by the landmark survival studies with statins in primary and secondary CAD prevention. Perhaps, if this finding is confirmed by larger studies, HRV level may prove to be a useful tool for risk-stratification and treatment guide in high-risk patients with hypercholesterolaemia, regardless of CAD.

Comparison of four definitions of the metabolic syndrome in a Greek (Mediterranean) population

Abstract Background: There is a need to evaluate the prevalence of metabolic syndrome (MetS) diagnosed by the new Joint Interim Societies (JIS) MetS definition. The JIS definition was compared with three previous definitions to assess their ability to predict cardiovascular disease (CVD) risk. Methods: A cross-sectional analysis of a representative sample of Greek adults (n  = 9669) was performed to estimate the prevalence of MetS and CVD using the JIS vs. the three older definitions of MetS: the National Cholesterol Education Program-Adult Treatment Panel-III (NCEP-ATP-III), the International Diabetes Federation (IDF) and the American Heart Association/National Heart Lung and Blood Institute (AHA/NHLBI) definitions. Results: The age-adjusted MetS prevalence was 45.7%, 43.4%, 24.5% and 26.3% (ANOVA p  < 0.001) with the JIS, IDF, NCEP and AHA/NHLBI definitions. The prevalence of CVD was 11.4% in the whole study population and 17.6%, 18.3%, 23.3%, 22.6% and in subjects with MetS according to the JIS, IDF, NCEP and AHA/NHLBI definitions (ANOVA p  < 0.001). The prevalence of CVD was only 10.4% (i.e., lower than in the whole study population) in subjects with MetS according to the JIS but not according to the NCEP-ATP-III and AHA/NHLBI definitions (p  < 0.001 vs. subjects with MetS as defined by NCEP-ATP-III or AHA/NHLBI). Conclusions: When diagnosed according to the new JIS definition, the prevalence of MetS was high in a Greek Mediterranean cohort (nearly half of the adult population). The NCEP-ATP-III and AHA/NHLBI definitions were more predictive of CVD risk than the new JIS definition. These findings, though limited by the cross sectional analysis, may have implications regarding the choice of the definition to diagnose MetS.

Prevalence of atherosclerotic vascular disease among subjects with the metabolic syndrome with or without diabetes mellitus: the METS-GREECE Multicentre Study

SUMMARY Aims: To estimate the prevalence of vascular disease (coronary heart disease/stroke/peripheral arterial disease) in individuals with the metabolic syndrome (MetSyn) with or without diabetes mellitus (DM) when compared with subjects without the MetSyn. Patients and methods: A cross-sectional analysis of a representative sample of Greek adults (n = 4153), men and women (49% and 51%, respectively), living in urban, semi-urban and rural areas (54%, 25% and 21%, respectively). The National Cholesterol Education Program – Adult Treatment Panel III definition of the MetSyn was used. Results: The age-adjusted prevalence of the MetSyn was 23.6% [95% confidence interval (CI) = 22.4%–25.1%]; this was similar in men and women. The fully adjusted prevalence of vascular disease in those with the MetSyn (n = 984) was 29.4%, significantly higher than in those without (n = 3169, 9.6%, p < 0.0001), while subjects without both the MetSyn and DM had the lowest vascular disease prevalence (n = 3035, 8.9%). Subjects with the MetSyn but no DM (n = 674) had a vascular disease prevalence of 24.1% ( p < 0.0001 vs. those without the MetSyn), which was similar to that in subjects with DM without the MetSyn (n = 134, 25.4%), but lower than in those with both the MetSyn and DM (n = 310, 40.7%, p < 0.0001 vs. all). In comparison to those without the MetSyn [odds ratio (OR) = 1], the ORs of prevalent vascular disease, after multivariate analysis for age, sex and components of the MetSyn, and antiatherosclerotic drugs were: all MetSyn = 1.94 (95% CI = 1.35–2.47), with both MetSyn and DM = 3.04 (95% CI = 1.98–4.11) and with MetSyn but no DM = 1.48 (95% CI = 1.12–1.92). Conclusions: The prevalence of vascular disease was markedly increased in the presence of the MetSyn. Those with both the MetSyn and DM had the highest prevalence of vascular disease, followed by those with the MetSyn without DM. Probably MetSyn without DM should be considered as a coronary heart disease-risk equivalent in future guidelines. This initiative would reset treatment targets and potentially provide additional benefit in patients with the MetSyn.

Early benefit from structured care with atorvastatin in patients with coronary heart disease and diabetes mellitus - A subgroup analysis of the GREek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) Study

This is a prospective evaluation of the effect of structured care of dyslipidemia with atorvas tatin (strict implementation of guidelines) versus usual care (physicians standard of care) on morbidity and mortality of patients with coronary heart disease (CHD) and diabetes mellitus (DM). From 1600 consecutive CHD patients randomized to either form of care in the GREek Atorvastatin and CHD Evaluation Study (GREACE), 313 had DM: 161 in the structured care arm and 152 in the usual care arm. All patients were followed up for a mean of 3 years. In the structured care group, patients were treated with atorvastatin to achieve the National Cholesterol Education Program (NCEP) low-density lipoprotein cholesterol (LDL-C) treatment goal of < 2.6 mmol/L (100 mg/dL). Primary endpoints were all-cause and coronary mortality, coronary morbidity, and stroke. In the structured care group, 156 patients (97%) were taking atorvastatin (10-80 mg/day; mean, 23.7 mg/day) throughout the study; the NCEP LDL-C treatment goal was reached by 150 patients (93%). Only 17% (n = 26) of the usual care patients were on long-term hypolipidemic drug treatment and 4% (n = 6) reached the NCEP LDL-C treatment goal. During the study, 46 of 152 (30.3%) CHD patients with DM on usual care experienced a major vascular event or died versus 20 of 161 (12.5%) patients on structured care; relative risk reduction (RRR) 58%, p < 0.0001. RRR for all-cause mortality was 52%, p = 0.049; coronary mortality 62%, p = 0.042; coronary morbidity 59%, p < 0.002; and stroke 68%, p = 0.046. Event rate curves started deviating from the sixth treatment month and the RRR was almost 60% by the 12th month. RRRs remained at that level until the end of the study, when they became statistically significant. The cost/life-year gained with structured care was estimated at US

Effects of simvastatin and ciprofibrate alone and in combination on lipid profile, plasma fibrinogen and low density lipoprotein particle structure and distribution in patients with familial combined hyperlipidaemia and coronary artery disease.

6200. In CHD patients with DM, structured care of dyslipidemia with atorvastatin to achieve the NCEP LDL-C treatment goal, reduces all-cause and coronary mortality, coronary morbidity, and stroke by more than one half within a 3-year period, in comparison to usual care. Clinical benefit is manifested as early as the sixth month of treatment.