Greek Atorvastatin And Coronary Heart Disease Evaluation Research Articles

Combination of Statin Plus Renin Angiotensin System Inhibition for the Prevention or the Treatment of Atherosclerotic Cardiovascular Disease

Statins effectively reduce cardiovascular disease (CVD) morbidity and mortality. However, even after low-density lipoprotein cholesterol goal attainment there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the renin-angiotensin system (RAS) was investigated. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE), Japanese Coronary Artery Disease (JCAD), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and The Assessing the Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone. This benefit seems to be related to effects on endothelial function, vascular inflammation and the initiation, progression and rupture of atheromatous plaques. These effects are, at least in part, driven by mediators, the microRNAs (miRs), that are implicated in the pathogenesis and clinical manifestations of atherosclerosis (e.g. restoration of endothelial function and attenuation of vascular inflammation). Some miRs are favourably affected by statins and others by RAS inhibition. There is a miR family (miR-146a/b), related to coronary artery plaque destabilization that is beneficially affected by both statins and RAS inhibition. Statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, metabolic syndrome, and/or diabetes to maximize clinical benefit.

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

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. 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. 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.

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

IntroductionThe 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 methodsThe 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 patient's choice outside the hospital.ResultsIn 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.ConclusionsAll 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.

Clinical Perspective: Statins and the Liver—Harmful or Helpful?

The safety of 3-hydroxy-3-methylglutaryl co-enzyme A (HMG-CoA) reductase inhibitors (statins) remains very much in the news, with recent regulatory alerts issued about the potential for effects on memory loss, an increased risk of type 2 diabetes, myopathy, and possible drug interactions involving HIV and hepatitis C protease inhibitors [1–3]. Although the US Food and Drug Administration (FDA) currently considers serious statinrelated liver injury to be a rare and unpredictable event [1], it nevertheless remains an important concern among physicians and patients alike. Moreover, the risk of adverse hepatic events receives renewed emphasis with each new case series that appears in the literature. Indeed, the proportion of patients who are not being prescribed statins because of the potential for adverse hepatic events, but who might otherwise benefit from their cardioprotective effects, is substantial [4]. A reading of the recent published literature contains a not so subtle war of words over the risk and magnitude of statin-related hepatotoxicity [5–14]. It almost appears as if each new case series of statin-associated hepatic injury [5, 6, 15] can be matched with or accompanied by editorial comments to place the risk into perspective [11–13]. As a case in point, the authors of a recent Icelandic case series of statin-associated liver injury appearing in Digestive Diseases and Sciences suggest that the risk of jaundice seen with statins is substantially higher than has been previously estimated, and call for increased vigilance when statins are prescribed, while they chide the author of a number of editorials who has opined that statin-induced hepatotoxicity is no more than a ‘‘myth’’ [5]. In his editorial retorts [11–13], Bader’s choice of words regarding the safety of statins is based on the fact that asymptomatic aminotransferase elevations are not an accurate reflection of hepatic injury, as similar elevations have also been noted in placebo recipients. This is also echoed by a recent safety update by FDA which finds that the ‘‘routine periodic monitoring of serum ALT does not appear to detect or prevent serious liver injury in association with statins’’ [1]. Bader’s opinions are bolstered by evidence arguing against a significant incidence of severe hepatotoxicity from statins, including the report of an expert panel of hepatologists who concluded that abnormal liver-associated enzymes (LAEs) associated with statins are not evidence for hepatic dysfunction [14], and that no consistent histologic picture has emerged. Furthermore, Bader contends that given the extensive usage of statins worldwide for more than two decades, if there were one or more patterns of hepatotoxicity that could be definitively linked to statins, they would certainly have been identified long before now [11]. In an accompanying editorial to the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study [16], Bader reiterates his opinion that statins have only very rarely been implicated in causing liver injury, and he bemoans the fact that most clinicians still base their concern about statin-associated liver injury on the warnings in their prescribing information [12]. Indeed, as recently as 2005, many physicians were still reluctant to prescribe a statin to patients with only minimal ALT elevations [4]. Bader infers that a few isolated published reports are still capable of perpetuating the ‘‘myth of statin-induced hepatotoxicity.’’ To the casual reader, such contrasting views may be a source of confusion and even consternation. Is statin J. H. Lewis (&) Georgetown University Medical Center, Washington, DC, USA e-mail: LEWISJH@gunet.georgetown.edu

Letter to Editor: Effects of Losartan vs. Enalapril on the Markers of Metabolic Syndrome

To the Editor, Al-Thanoon et al. reported that several markers of metabolic syndrome (MetS) were improved by the administration of losartan (50 mg/day) or enalapril (20 mg/day).1 A significant increase in high density lipoprotein cholesterol (HDL-C) was noted only with losartan.1 Some comments may be of interest. The Losartan Intervention for Endpoint reduction (LIFE) trial included 9,193 hypertensive patients with electrocardiographically documented left ventricular hypertrophy.2 These patients were randomized to losartan or atenolol and followed for 4.7 years. Losartan was superior to atenolol in reducing cardiovascular (CV) and total mortality.2 In this study, losartan blunted the decrease in HDL-C and this was associated with fewer composite endpoints compared with atenolol.3 Also, in the LIFE trial, the rise in serum uric acid (SUA) levels was attenuated by losartan and has been related to CV outcomes.4 Losartan is the only angiotensin II type 1 receptor blocker with a hypouricemic effect.5 SUA levels are raised in MetS,6 and may predict CV events.7 The decrease in SUA levels by drugs used for vascular disease prevention (e.g. atorvastatin) is associated with a reduced risk of CV events.8 Therefore, it would be useful to know if there were any changes in SUA levels in the Al-Thanoon et al. study.1 Non-alcoholic liver disease (NAFLD) is considered a manifestation of MetS which is also associated with raised SUA levels.9 Even abnormal liver function tests (LFTs) have been linked with increased vascular risk.10 A post hoc analysis of the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study included 437 patients with coronary heart disease and moderately elevated (<3 × the upper limit of normal) LFTs [alanine (ALT) and aspartate aminotransferase (AST) activities].11 These patients experienced a greater CV benefit from atorvastatin compared with those with normal AST/ALT activities.11 Therefore, it would be interesting to know whether weight reduction together with antihypertensive treatment was associated with changes in AST/ALT activities in the Al-Thanoon et al. study.1 The weight loss (4.2 and 3.0 kg in the losartan and enalapril group, respectively) was quite marked over this 2 month study.1 Did the patients receive lifestyle advice? Also, it is important to consider that any effects on SUA, HDL-C and LFTs might be weight-related.

Mechanisms Linking Nonalcoholic Fatty Liver Disease with Coronary Artery Disease

Nseiretal.[1]discusstheassociationbetweennon-alcoholicfatty liver disease (NAFLD) and coronary artery disease(CAD). Some comments may be of interest.A post hoc analysis of the Greek Atorvastatin andCoronary Heart Disease Evaluation (GREACE) studyincluded 437 patients with CAD, dyslipidemia (low-densitycholesterol [2.6 mmol/l) and NAFLD [2]. NAFLD wasassumed in patients with moderately elevated transaminaseactivities (\39 the upper limit of normal) together withrelevant ultrasonographic findings, after excluding othercauses of abnormal liver function tests (LFTs) [2]. Patientswith abnormal LFTs treated with statins had fewer cardio-vascular (CV) events compared with those not on statins(68% relative risk reduction, p\0.0001) [2]. Interestingly,the CV benefit from statin treatment was greater(p = 0.0074) in patients with abnormal than in those withnormal baseline LFTs (39% relative risk reduction,p\0.0001) [2]. Transaminase activities were reduced inpatients treated with statins while further rises were noted inthose not on statins [2]. However, these promising findingshave limitations, including the post hoc analysis and smallnumber of patients. Furthermore, liver biopsy, the ‘‘goldstandard’’ for the diagnosis of NAFLD, was not performed.We agree with Nseir et al. [1] that non-esterified fattyacids (NEFAs) may play a role in atherogenesis. In thiscontext, NEFAs inhibit the synthesis and accelerate thedegradation of prostacyclin (PGI

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

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

Cholesterol-lowering therapy for the treatment of nonalcoholic fatty liver disease

To review recent human trials assessing cholesterol-lowering agents in nonalcoholic fatty liver disease (NAFLD). Four randomized controlled trials (RCTs) assessed statins in NAFLD. In the only RCT with post-treatment biopsy, simvastatin did not change liver histology. In the remaining RCTs, atorvastatin was well tolerated, significantly improved radiological/biochemical markers of steatosis and plasma lipids, with neutral effects on glucose metabolism; in the Greek Atorvastatin and Coronary Heart Disease Evaluation (GREACE) study, atorvastatin reduced incident cardiovascular disease compared with both untreated NAFLD patients and with statin-treated patients without NAFLD. Ezetimibe was evaluated in two uncontrolled trials and two RCTs, consistently improving liver histology and plasma lipids, whereas glucose metabolism was generally unaffected; however, HbA1c increased with ezetimibe in one RCT. From the analysis of available trials, it emerges that cholesterol-lowering agents may considerably benefit NAFLD patients. Statins are well tolerated, and atorvastatin improved surrogate markers of liver disease, whereas their effect on liver histology is unknown. Furthermore, the GREACE study was the first trial to show clinical benefit from the use of a pharmacological agent in NAFLD. Ezetimibe improved liver histology. The benefit of combination therapy, as well as the safety on glucose metabolism, need further evaluation.

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

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. 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. 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). 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. None.

Statin-Induced Increase in HDL-C and Renal Function in Coronary Heart Disease Patients§

BackgroundLittle is known about the potential of statin-induced high-density lipoprotein cholesterol (HDL-C) increase to improve renal function in coronary heart disease (CHD) patients.Methods and Results In thispost hocanalysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study we investigated the effect of HDL-C increase after statin treatment on renal function. From a total of 1,600 patients, 880 were on various statins (mainly atorvastatin) and 720 were not. Other secondary prevention therapies were similar in the 2 groups. After a 3 year follow up, the lipid profile was unchanged in the statin untreated group and estimated glomerular filtration rate (eGFR) was reduced by 5.1% compared with baseline (P<0.0001). In contrast, in the statin treated group non-HDL-C was reduced by 43%, HDL-C was increased by 7% and there was a significant increase in eGFR compared with baseline by 9.8% (P<0.0001). In multiple regression analysis, the mean 7% increase in HDL-C in the treated arm during the entire study was associated with a 5.6% increase in eGFR recorded after the 6th week of treatment. The odds ratio of eGFR increase with every 5% statin-induced rise in HDL-C was 1.78 (95% confidence interval 1.19-3.34; P=0.001).ConclusionsStatin treatment significantly improved renal function. Statin-induced HDL-C increase significantly and independently contributed to this improvement. This finding supports the concept that improving lipid variables other than low density lipoprotein cholesterol is also beneficial to preserving renal function.

Atorvastatin

An association between hypercholesterolaemia and ischaemic stroke has not yet been clearly defined by observational studies. In clinical trials, however, cholesterol-lowering treatments appear to consistently reduce stroke risk. Data are now available from various primary prevention studies - ALLHAT-LLT (Antihypertensive and Lipid-Lowering treatment to prevent Heart Attack, Lipid-Lowering Therapy), ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial, Lipid-Lowering Arm), CARDS (Collaborative Atorvastatin Diabetes Study, WOSCOPS (West of Scotland COronary Prevention Study) - and secondary prevention studies - 4S (Scandinavian Simvastatin Survival Study), CARE (Cholesterol and Recurrent Events), GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation), HPS (Heart Protection Study), LIPID (Long-term Intervention with Pravastatin in Ischaemic Disease), MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels), TNT (Treating to New Targets) - confirming the ability of statins to reduce stroke risk. Regarding primary prevention, post hoc analyses showed pravastatin reduced the relative risk of stroke by 9-11% (not statistically significant) in the ALLHAT-LLT and WOSCOPS trials, whereas atorvastatin reduced this risk by 27-48% in the ASCOT-LLA (p = 0.024) and CARDS trials. It remains to be established in prospective studies whether cholesterol-lowering is effective in the primary prevention of stroke. Regarding secondary prevention, in five placebo-controlled studies (4S, CARE, HPS, LIPID, MIRACL) involving a total of >40 000 patients with coronary heart disease (CHD), statin therapy reduced the relative risk of fatal or nonfatal stroke by 19-50% (p < or = 0.048); the largest decrease was produced by atorvastatin in the MIRACL study (-50%, p = 0.045). In addition, high-dosage atorvastatin reduced stroke risk by 25% (p = 0.02) relative to lower-dosage therapy in the TNT trial, and by 47% (p = 0.034) relative to 'usual' care in the GREACE study. A post hoc analysis of data for 3280 HPS study participants who had had a previous stroke revealed that simvastatin reduced major vascular events by 20% (p = 0.001).The SPARCL study assessed the secondary preventive efficacy of atorvastatin versus placebo in 4731 patients with a history of stroke or transient ischaemic attack (TIA), but without CHD. Atorvastatin reduced the adjusted relative risk of fatal or nonfatal stroke by 16% (p = 0.03), and that of fatal stroke alone by 43% (p = 0.03). Among secondary study endpoints, atorvastatin reduced the relative risks of stroke and TIA (-23%; p < 0.001), TIA alone (-26%; p = 0.004), and ischaemic stroke (-22%; p = 0.01). Overall, SPARCL study findings suggest that intensive atorvastatin therapy should be started immediately after a stroke or TIA. In summary, atorvastatin has developed a well defined role in the primary and secondary prevention of cerebrovascular disease, and appears to have a particularly prominent place in preventing such disease in CHD patients, and in the post-stroke and post-TIA setting in patients without CHD.

Atorvastatin Efficacy in the Prevention of Cardiovascular Events in Patients with Diabetes Mellitus and/or Metabolic Syndrome

Several large-scale clinical trials have assessed the efficacy of atorvastatin in the primary and secondary prevention of cardiovascular events in patients with diabetes mellitus and/or metabolic syndrome. In primary prevention, CARDS (Collaborative Atorvastatin Diabetes Study) showed that atorvastatin 10 mg/day (vs placebo) reduced relative risk of the composite primary endpoint (acute coronary heart disease [CHD] events, coronary revascularisation, or stroke) by 37% (p = 0.001). This decrease was similar to decreases in major cardiovascular events in the ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm) trial and HPS (Heart Protection Study). However, in CARDS, atorvastatin efficacy was evident as early as 6 months after starting treatment, whereas in HPS, simvastatin efficacy was noticeable only from about 15-18 months after starting treatment. In the ASCOT-LLA trial, in 2226 hypertensive diabetic patients without previous cardiovascular disease, atorvastatin (vs placebo) reduced the relative risk of all cardiovascular events and procedures by 25% (p = 0.038). In secondary prevention, substudies of the GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation), TNT (Treating to New Targets) and PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) trials reported results for the approximately 15-25% of study participants who had diabetes. In the GREACE substudy, atorvastatin (vs physicians' standard care) significantly reduced the relative risk of total mortality by 52% (p = 0.049), coronary mortality by 62% (p = 0.042), coronary morbidity by 59% (p < 0.002) and stroke by 68% (p = 0.046). In the TNT substudy, incidence of the primary endpoint was significantly lower in diabetic patients treated with atorvastatin 80 mg/day rather than 10 mg/day (13.8% vs 17.9%; relative risk 0.75; p = 0.026). In the PROVE-IT substudy, a significantly lower incidence of acute cardiac events was reported for atorvastatin versus pravastatin recipients (21.1% vs 26.6%; p = 0.03) and, therefore, an absolute risk reduction of 5.5% was associated with atorvastatin therapy. ASPEN (Atorvastatin Study for Prevention of coronary heart disease Endpoints in Non-insulin-dependent diabetes mellitus) - a mixed primary and secondary prevention trial in diabetic patients - found that a 29% lower low-density lipoprotein-cholesterol level was seen with atorvastatin than placebo at endpoint (p < 0.0001); however, the reduction in composite primary endpoint of major cardiovascular events (cardiovascular mortality, nonfatal major cardiovascular event or stroke, and unstable angina requiring hospitalisation) with atorvastatin (13.7% vs 15.0% with placebo), and reduction in acute myocardial infarction relative risk of 27% with atorvastatin were not statistically significant. In CHD patients with metabolic syndrome (n = 5584) in a sub-analysis of the TNT trial, intensive versus lower-dosage atorvastatin therapy reduced the relative risk of major cardiovascular and cerebrovascular events by 29% (p < 0.0001). The analysis also revealed that CHD patients with, rather than those without, metabolic syndrome had a 44% greater level of absolute cardiovascular risk, thus clearly underscoring the clinical feasibility of administering intensive lipid-lowering therapy to CHD patients with metabolic syndrome. In summary, several patient populations, from definitive, large-scale studies, are now available to corroborate the integral place of atorvastatin--in line with various regional and internationally accepted disease management guidelines--in the primary and secondary prevention of cardiovascular events in patients with diabetes and/or metabolic syndrome.

Atorvastatin Efficacy in the Primary and Secondary Prevention of Cardiovascular Events

Atorvastatin has been extensively studied in the primary and secondary prevention of cardiovascular events, and may have some clinical advantages over various other statins in these respects. The principal primary prevention study of atorvastatin, ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm), revealed that atorvastatin reduced the relative risk of primary coronary heart disease (CHD) events by 36% (p = 0.0005) compared with placebo in patients with hypertension. Much published data confirm the secondary preventive benefits of atorvastatin in various clinical settings. The IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) and TNT (Treating to New Targets) trials demonstrate the preventive efficacy of atorvastatin in patients with stable CHD. Relative to simvastatin (in the IDEAL trial) and low-dosage atorvastatin (in the TNT trial), intensive atorvastatin therapy (80 mg/day) reduced the risk of nonfatal myocardial infarction (MI) by 17-22% (p < or = 0.02). Furthermore, the ALLIANCE (Aggressive Lipid-Lowering Initiation Abates New Cardiac Events) and GREACE (GREek Atorvastatin and Coronary-heart-disease Evaluation) trials highlight the benefits of atorvastatin in the 'real world' setting in patients with stable CHD. Compared with 'usual' care, atorvastatin reduced the risk of nonfatal MI by 47-59% (p < or = 0.0002).Moreover, the MIRACL (Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering), PROVE-IT (PRavastatin Or atorVastatin Evaluation and Infection Therapy) and IDEAL-ACS (Acute Coronary Syndromes) studies outline the benefits of high-dosage atorvastatin therapy started within 24-96 hours, 10 days or 2 months, respectively, of an acute coronary syndrome. Relative to placebo, pravastatin and simvastatin, atorvastatin reduced the risk of death or major cardiovascular events by 16-18% (p < or = 0.048). In patients undergoing revascularisation procedures, the AVERT (Atorvastatin VErsus Revascularisation Treatment) study revealed that 18 months' administration of atorvastatin 80 mg/day was at least as effective as angioplasty plus usual care in reducing the risk of ischaemic events in low-risk patients with stable coronary artery disease. Furthermore, the ARMYDA (Atorvastatin for Reduction in MYocardial DAmage during angioplasty) and ARMYDA-3 trials showed that 7 days' administration of atorvastatin 40 mg/day before coronary intervention significantly reduced the risks of periprocedural myocardial damage (ARMYDA), postprocedural MI (p = 0.025; ARMYDA) and atrial fibrillation (p = 0.003; ARMYDA-3) versus placebo. In addition, it has been reported that C-reactive protein levels and the combined incidence of cardiovascular events (death, MI and target segment revascularisation during the 6-month follow-up) were significantly higher in coronaropathic patients undergoing non-surgical revascularisation procedures (stent implantation) not receiving statin therapy compared with those treated with atorvastatin (80mg). Overall, therefore, the marked efficacy of atorvastatin in the primary and secondary prevention of cardiovascular events underscores the pivotal place that this statin has in general cardiovascular disease management, and suggests even greater potential clinical utility for the drug in some clinical settings.

Effect of statin treatment on renal function and serum uric acid levels and their relation to vascular events in patients with coronary heart disease and metabolic syndrome: A subgroup analysis of the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study

Metabolic syndrome (MetS) is associated with increased risk for both vascular and chronic kidney disease. Whether statins ameliorate these risks is not established. This post hoc analysis of the GREek Atorvastatin and Coronary heart disease (CHD). Evaluation (GREACE) examines the effect of statins on estimated glomerular filtration rate (e-GFR) and serum uric acid (SUA) levels and their relation to vascular events in CHD patients with MetS. MetS patients were divided into two groups: Group A (n = 365) received lifestyle advice, target-driven treatment with statins (mainly atorvastatin) and treatment for hypertension and elevated glucose. Group B (n = 347) received the same except for statins. Patients without MetS were divided into those who received treatment similar to Group A and Group B [Groups C (n = 504) and D (n = 384), respectively]. All patients were followed for 3 years. A total of 12.1% of patients in Group A experienced a vascular event vs 28% in Group B; risk ratio (RR) 0.43, 95% confidence interval (CI) 0.20-0.64, P < 0.0001, while in those without MetS (Group C vs Group D), the respective RR was 0.59, 95% CI 0.41-0.79, P < 0.0001. In Group A, e-GFR increased by 13.7% and SUA levels fell by 8.9%, while in Group B e-GFR was reduced by 5.8% and SUA increased by 4.3% (P < 0.005). Stepwise regression analysis showed that these changes were independently related to vascular events. Among CHD patients, those with MetS benefited more from statin treatment than those without MetS. This benefit could be partially attributed to favourable changes in e-GFR and SUA levels probably induced by statin treatment.

Effect of statins and aspirin alone and in combination on clinical outcome in dyslipidaemic patients with coronary heart disease. A subgroup analysis of the GREACE study

Declaration of interest: The GREACE study was conducted independently; no Company or Institution has supported it financially. Some of the authors have attended conferences and participated in other trials sponsored by various pharmaceutical companies.We assessed the possible ‘synergy’ of statins and aspirin (ASA) in reducing vascular events in patients with coronary heart disease, in a post hoc analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. All patients (n = 1600) were divided into four groups according to long-term treatment: Group A (n = 787; statin + ASA), B (n = 93; statin − no ASA), C (n = 599; no statin − on ASA) and D (n = 121; no statin − no ASA). From all patients 692 were either on a statin or ASA monotherapy (Groups B + C). Relative risk reductions (RRRs) in ‘all events’ (primary endpoint) between groups were assessed. During the 3-year follow-up there were 292 cardiovascular events; 92 (12% of patients) in Group A, 14 (15%) in group B, 144 in Group C (24%) and 42 events in Group D (35%). The total number of events in Group B + C was 158 (23%). The RRRs in the primary endpoint were: Group A versus B 24% (P = 0.1912), A versus C 51% (P < 0.0001), A versus B + C 49% (P<0.0001) and A versus D 71% (P < 0.0001). The RRRs in Group B versus C was 36% (P = 0.0431) and B versus D 57% (P = 0.0012), while in C versus D 33% (P = 0.0084). Our findings show that statins and ASA have an additive effect in reducing cardiovascular events. Aggressive statin use in the absence of ASA also substantially reduced cardiovascular events. Treatment with ASA in the absence of statin use reduced clinical events in comparison to patients not treated with either drug.

Relationship between LDL-C and non-HDL-C levels and clinical outcome in the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study

SUMMARYBackground: Although available guidelines suggest reducing low-density lipoprotein cholesterol (LDL-C) to below 100 mg/dL (2.6 mmol/L), the importance of target-oriented therapy remains controversial. To assess whether achieving guideline-based targets is of benefit, the relationship between clinical outcomes and lipid levels (baseline and on-study) was evaluated in the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study. This study demonstrated significant reductions in morbidity and mortality associated with active dose titration of atorvastatin and structured management of dyslipidaemia.Methods and results: Intention-to-treat analysis (Cox proportional hazards model) was used to assess the relationship between lipid values and coronary events. Higher levels of LDL-C at baseline were associated with a greater risk of subsequent events among patients randomized to usual care. Reducing the LDL-C and the non-high density lipoprotein cholesterol (non-HDL-C) level to the National Cholesterol Educational Program (NCEP) Adult Treatment Panel (ATP) III goals required greater doses of atorvastatin for the higher baseline quartile of LDL-C. During the study there was a greater reduction in the risk of coronary heart disease (CHD) events in atorvastatin-treated patients who were in the highest quartile of LDL-C at baseline, after achieving the LDL-C treatment goal, in comparison to the usual care patients in the highest baseline LDL-C quartile.Conclusions: Achieving the NCEP ATP III LDL-C and non-HDL-C goals by titrating up the dose of atorvastatin was associated with a significant reduction in vascular events in patients with CHD. The greatest benefit was seen in those patients with the highest baseline LDL-C levels.

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...

Effect of statins versus untreated dyslipidemia on serum uric acid levels 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 the effect of dyslipidemia on serum uric acid (SUA) levels, and less is known about the effect of statin treatment on them. The GREek Atorvastatin and Coronary-heart-disease Evaluation study suggested that a mean atorvastatin dose of 24 mg/d achieves the National Cholesterol Educational Program treatment goals and significantly reduces morbidity and mortality in patients with coronary heart disease (CHD) in comparison to the usual care. Here, we report the time course of SUA levels in usual-care patients undertreated for their dyslipidemia (12% were administered statins) in comparison to structured-care patients treated with atorvastatin in the vast majority (98%). Methods: Mean on-study SUA levels (up to 48 months) were compared with those at baseline by using analyses of variance to assess differences over time within and between treatment groups. Cox multivariate analysis was used to investigate whether changes in SUA levels during the study were clinically relevant. Results: All patients had normal renal function at baseline; serum creatinine (SCr) levels less than 1.3 mg/dL (<115 μmol/L) and moderately elevated SUA levels (mean, 7.1 ± 0.9 [SD] mg/dL [425 ± 52 μmol/L]; upper normal limit, 7.0 mg/dL [415 μmol/L]). Usual-care patients (n = 800) showed an increase in SUA levels by 3.3% (P < 0.0001). Structured-care patients (n = 800) had an 8.2% reduction in SUA levels (P < 0.0001). In all patients not administered diuretics (n = 1,407), SUA level changes showed a positive correlation with changes in SCr levels (r = 0.82; P < 0.0001) and an inverse correlation with estimated glomerular filtration rate (r = −0.77; P < 0.0001). After adjustment for 19 predictors of all CHD-related events, Cox multivariate analysis involving backward stepwise logistic regression showed a hazard ratio (HR) of 0.89 (95% confidence interval [CI], 0.78 to 0.96; P = 0.03) with every 0.5-mg (30-μmol/L) reduction in SUA level, an HR of 0.76 (95% CI, 0.62 to 0.89; P = 0.001) with every 1-mg (60-μmol/L) reduction, an HR of 1.14 (95% CI, 1.03 to 1.27; P = 0.02) with every 0.5-mg increase, and an HR of 1.29 (95% CI, 1.17 to 1.43; P = 0.001) with every 1-mg increase in SUA levels. Conclusion: Data suggest that SUA level is an independent predictor of CHD recurrent events. Atorvastatin treatment significantly reduces SUA levels in patients with CHD, thus offsetting an additional factor associated with CHD risk.

Effect of atorvastatin on highdensity lipoprotein cholesteroland its relationship withcoronary events: a subgroupanalysis of the GREekAtorvastatin and Coronary-heart-disease Evaluation (GREACE) Study

SUMMARYObjective: To investigate the relationship between changes in high density lipoprotein cholesterol (HDL-C) levels after statin treatment and the risk for coronary heart disease (CHD)-related events in the secondary CHD prevention GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. These findings suggested that dose titrationwith atorvastatin (10-80mg/day, mean 24mg/day) achieves the National Cholesterol Educational Program treatment goals and significantly reduces morbidity and mortality, in comparison to usual care.Methods: Analysis of variance was used to assess the effect of atorvastatin on HDL-C overtime (up to 48 months) in 1600 CHD patients. The time-dependent multivariate Cox predictive model, involving backward stepwise logistic regression, was used to evaluate the relation between coronary events and HDL-C changes.Results: The mean increase in HDL-C levels during the study was 7%. All doses of atorvastatin significantly increased HDL-C levels. Increases were greater in men (7.8 vs 6.1%; p = 0.02), in combined hyperlipidaemia (7.9 vs 6.4% for hypercholesterol-aemia; p = 0.04), and in the lower baseline HDL-C quartile (9.2 vs 5.3%, 1st vs 4th quartile; p = 0.001). After adjustment for 24 predictors of coronary events, multivariate analysis revealed a Hazards Ratio of 0.85 (95% confidenceinterval 0.76-0.94; p = 0.002) for every 4 mg/dL (0.1 mmol/L) increase in HDL-C.Conclusions: There was a significant beneficial effect on HDL-C levels across the dose range of atorvastatin. Clinical outcomes in the structured care arm of GREACE were determined in part by the extent of atorvastatin-induced HDL-C increase. This effect was independent from benefit induced by low density lipoprotein cholesterol (LDL-C) reduction, suggesting that the CHD risk reduction associated with a rise in a low HDL-C at baseline remains significant under aggressive (-46%) LDL-C lowering conditions. However, the relationship between HDL-C and vascular risk may be weaker when LDL-C levels are aggressively lowered.

Statins and renal function in patients with diabetes mellitus

SUMMARYLipids may adversely affect renal function. The recently published MRC/BHF Heart Protection Study (HPS) subgroup analysis showed that simvastatin significantly reduced the fall in glomerular filtration rate in high-risk patients with and without diabetes mellitus. These findings are in line with those ofsmaller earlier studies, including the GREek Atorvastatin and Coronary heart disease Evaluation (GREACE) Study. Lipid lowering trials need to consider that changes in renal function may occur. Renal and ischaemic heart disease may progress in parallel and statins may be beneficial to both organs.