Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Research Articles

Association of Nonfasting vs Fasting Lipid Levels With Risk of Major Coronary Events in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid Lowering Arm

Recent guidelines have recommended nonfasting for routine testing of lipid levels based on comparisons of nonfasting and fasting populations. However, no previous study has examined the association of cardiovascular outcomes with fasting vs nonfasting lipid levels measured in the same individuals. To compare the association of nonfasting and fasting lipid levels with prospectively ascertained coronary and vascular outcomes and to evaluate whether a strategy of using nonfasting instead of fasting lipid level measurement would result in misclassification of risk for individuals undergoing evaluation for initiation of statin therapy. This post hoc prospective follow-up of a randomized clinical trial included 8270 of 10 305 participants from the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) with nonfasting and fasting lipid levels measured 4 weeks apart (including 6855 participants with no prior vascular disease) (median follow-up, 3.3 years; interquartile range, 2.8-3.6 years). Data were collected from February 1, 1998, to December 31, 2002, and analyzed from February 1, 2016, to November 30, 2018. Multivariable Cox models, adjusted for cardiovascular risk factors, were calculated for 40-mg/dL (1-mmol/L) higher values of nonfasting and fasting lipids. The trial's primary end point consisted of major coronary events (nonfatal myocardial infarction [MI] and fatal coronary heart disease [212 events]). Secondary analyses examined atherosclerotic cardiovascular disease (ASCVD) events (including MI, stroke, and ASCVD death [351 events]). Among the 8270 participants (82.1% male; mean [SD] age, 63.4 [8.5] years), nonfasting samples had modestly higher triglyceride levels and similar cholesterol levels compared to fasting samples. Associations of nonfasting lipid levels with coronary events were similar to those for fasting lipid levels. For example, adjusted hazard ratios (HRs) per 40-mg/dL of low-density lipoprotein cholesterol were 1.32 (95% CI, 1.08-1.61; P = .007) for nonfasting levels and 1.28 (95% CI, 1.07-1.55; P = .008) for fasting levels. For the primary prevention group, adjusted HRs were 1.42 (95% CI, 1.13-1.78; P = .003) for nonfasting levels and 1.37 (95% CI, 1.11-1.69; P = .003) for fasting levels. Results were consistent by randomized treatment arm (atorvastatin calcium, 10 mg/d, or placebo) and similar for ASCVD events. Concordance of fasting and nonfasting lipid levels for classifying participants into appropriate ASCVD risk categories was high (94.8%). Measurement of nonfasting and fasting lipid levels yields similar results in the same individuals for association with incident coronary and ASCVD events. These results suggest that routine measurement of nonfasting lipid levels may help facilitate ASCVD risk screening and treatment, including consideration of when to initiate statin therapy.

New clinical and pharmacological aspects of the use of atorvastatin for primary and secondary prevention of complications of cardiovascular diseases

The article discusses new data obtained in the course of several large observational studies evaluating the quality of prevention of cardiovascular diseases caused by atherosclerosis in the modern population. It also considers the the problem of insufficiently frequent use of lipid-lowering drugs in modern clinical practice. New data are presented on the benefits of using statins, in particular atorvastatin, for the purpose of not only secondary, but also primary prevention, as well as the preservation of the efficacy and safety of statin therapy over a long period. Possible benefits of using atorvastatin are discussed, including the possibility of more rapid achievement of the clinical effect that was reported during the randomized controlled clinical trial, which can play a role in the choice of certain statins in certain clinical situations. The recently published results of the analysis of data on the subjects of the ASCOT-LLA (Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm) study, which were obtained with long-term follow-up, are discussed. The article considers the new data on the probably excessively conservative approach to the selection of target levels of low-density lipoprotein cholesterol in the blood that were obtained during the large observational studies. The modern concept of “primary prevention” of cardiovascular diseases caused by atherosclerosis is considered. The recent data presented in the article include the features of the use of atorvastatin in clinical practice, which may be an additional reason for increasing the frequency of its use in clinical practice for the purpose of both secondary and primary prevention.

Dyslipidemia.

Dyslipidemia.

Editorial The effects of statins on blood pressure: current knowledge and future perspectives

Statin therapy has gained interest in the field of hypertension due to the potential role of different statin agents in blood pressure (BP) lowering [1–3]. The potential mechanisms involved include the downregulation of the angiotensin II-type 1 receptor, the decrease of vasoconstrictor endothelin-1 levels, and the increase in the endothelial production of nitric oxide (NO), an effect that is correlated with the upregulation of endothelial NO synthase expression [4–6]. Furthermore, we have recently reported the effects of statin treatment on endothelial function, oxidative stress and inflammation in patients with hypertension and normal cholesterol levels [7]. Yet, despite the beneficial effects shown by statins in hypertensive animal models as well as in small clinical studies, the results from meta-analyses and large clinical trials have been controversial. Indeed, the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) [8] demonstrated that the combination of amlodipine-based therapy and atorvastatin was highly effective in preventing cardiovascular (CV) endpoints in hypertensive patients at risk of CV disease, but the authors did not report any significant effect on BP [8]. However, it should be highlighted that the use of anti-hypertensive agents was left to the discretion of physicians during the trials [8]. Additional information comes from post-hoc analyses and meta-analyses, suggesting that statins could lower systolic blood pressure, particularly in patients with high blood pressure [9]; however, most studies had small sample sizes, were not blinded, and the time of observation was not long enough. In addition, several authors have emphasized that hypertension and hyperlipidaemia seem to be interrelated through common pathophysiological pathways [10] and it has been recently reported [11] that lipoprotein size and subclass concentrations, especially small, dense low-density lipoproteins (LDL), are associated with incident hypertension and may provide additional information to traditional CV risk factors [11]. In this view, it should be highlighted that the most important link between lipid metabolism and atherosclerosis is based on the formation of foam cells (the first step of plaque generation) from oxidized, small dense LDL [12]. Indeed, LDL are very heterogeneous particles, which comprise multiple distinct subclasses that differ in size, density, physico-chemical composition, metabolic and oxidative behaviour, as well as atherogenicity [13]. Increasing evidence suggests that both the “quality”, and probably especially the “quantity” of plasma lipids and lipoproteins influence CV risk, as reflected in the pro-atherogenic alterations that give rise to elevated levels of small, dense LDL. The pathophysiology, atherogenicity and clinical significance of these LDL particles have already been highlighted in the recent consensus statement of a European panel of experts [14, 15]. Owczarek et al. in the present issue of Archives of Medical Science [16] report no beneficial effects of simvastatin after 4 weeks of therapy on BP and heart rate after metoprolol injection in animal models (rats). The authors have already observed similar effects in two other studies with a 2-week period of statin administration [17, 18]. Yet, a reduction in heart rate and BP has been reported in patients with hypertension and type-2 diabetes with the concomitant administration of simvastatin and metoprolol [19], and other studies evaluated the effects of such combined therapy on C-reactive protein levels [20]. We cannot exclude that therapeutic modulation of enhanced inflammation and/or atherogenic dyslipidaemia may contribute to the beneficial effect shown by simvastatin on blood pressure, especially considering that the study by Owczarek et al. has some important limitations connected to the length of the intervention (only 4 weeks), the dose and the type of statin, and finally with the selection of hypertension drug: metoprolol, an old β1 receptor blocker without a nitric oxide-potentiating vasodilatory effect [16, 21]. In conclusion, as recently highlighted, there is more to predicting vascular disease than just established risk factors [22]. Patients with hypertension benefit from statin administration, independently of their plasma lipid levels, and independently of the influence on their BP. Inflammation and atherogenic dyslipidaemia may play a role [23–25]. Future well-designed clinical trials with carefully selected endpoints are needed in order to demonstrate whether statins definitely have an anti-hypertensive effect. Such studies should also investigate the synergistic effects of hypertension and atherogenic lipoproteins on CV risk.

“Risky Business”

Nobody can go back and start a new beginning, but anyone can start today and make a new ending. — —Maria Robinson Although the Framingham Risk Score forms the bedrock of coronary heart disease (CHD) risk prediction, it has several limitations that have been well documented.1 The clinician is left to manage a significant proportion of patients who have “low to intermediate” estimated risk but accrue the majority of CHD events because they form the majority (≈65%) of the population. Article p 382 To address these deficiencies in the prediction of risk, several investigators have included other markers of risk such as biomarkers related to inflammation, genotypes, or imaging tests with traditional risk factors to improve CHD risk prediction. These analyses have resulted in the creation of novel risk-prediction schemes such as the Reynolds risk score, which added family history and high-sensitivity C-reactive protein (hs-CRP) to blood pressure, smoking, total and high-density lipoprotein cholesterol, and hemoglobin A1C to predict risk.2 However, whether algorithms have used biomarkers such as hs-CRP, imaging tests such as coronary calcium score or carotid intima-media thickness, or novel genotypes such as the single-nucleotide polymorphism on chromosome 9p21, the improvements in risk prediction have been modest. Other investigators have suggested that anybody who is not at very low risk should get an imaging test to further stratify risk.3 On the other hand, there have been efforts to identify the “lifetime risk” of CHD for individuals in various age groups. The concept of lifetime risk was highlighted in the National Cholesterol Education Program Adult Treatment Panel (ATP) III guidelines4 and is an important one, especially for individuals who are young to middle-aged. Traditional risk factors become manifest more often in the 4th and 5th decades of life when the estimated lifespan based on …

Primary Prevention and Statins: Is It Just About Going to Class?

Primary Prevention and Statins: Is It Just About Going to Class?

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.

Combined Effects of Systolic Blood Pressure and Total Cholesterol on Cardiovascular Disease Risk

Half of all adult deaths (and much severe disability) are caused by cardiovascular diseases, and most of these deaths involve ischemic heart disease or stroke. The Asia-Pacific region accounts for about half of the global burden of cardiovascular disease and the proportion is likely to increase during the next few decades.1,2 Smoking and elevated levels of systolic blood pressure (SBP) and total blood cholesterol are major causes of cardiovascular disease,3 yet much of our knowledge about the associations between these risk factors and cardiovascular diseases comes from studies carried out in North American and western European countries. In most Asian countries, however, the mean levels of total cholesterol are lower than those found in Western countries and the incidence of coronary heart disease (CHD) is also lower, whereas the incidence of stroke, particularly hemorrhagic stroke, is higher. Article p 3384 The Asia Pacific Cohort Studies Collaboration report in this issue of Circulation investigates the combined effects of SBP and total cholesterol on risk of cardiovascular disease in a meta-analysis of 36 cohort studies (29 conducted in Asia and 7 from Australia and New Zealand) involving 380 000 individuals.4 This meta-analysis differs from previous studies in several ways: It is the largest study from this region, involving >3000 CHD events and 4000 stroke events; individual records were available for each of the participants in each study, with cause and age of death (if applicable); and information on several thousand repeat measurements of blood pressure and cholesterol made during prolonged follow-up allowed correction for “regression dilution.” These features …

Comparative Safety of Atorvastatin 80 mg Versus 10 mg Derived from Analysis of 49 Completed Trials in 14,236 Patients

Atorvastatin has been shown to reduce coronary events and revascularization procedures in patients with multiple risk factors for coronary heart disease. Recent studies with atorvastatin 80 mg support the overall safety of this dose during long-term treatment. However, physicians appear reluctant to use high doses of statins. A retrospective analysis of pooled data from 49 clinical trials of atorvastatin in 14,236 patients treated for an average period of 2 weeks to 52 months was conducted. The study compared the safety of atorvastatin 10 mg (n = 7,258), atorvastatin 80 mg (n = 4,798), and placebo (n = 2,180) and included analyses on treatment-associated adverse events; nonserious and serious adverse events related to the musculoskeletal, hepatic, and renal systems; the incidence of elevations of creatine kinase >10 times the upper limit of normal (ULN); and hepatic transaminases >3 times ULN. Percentages of patients experiencing > or =1 adverse event were similar across all 3 groups. Withdrawals due to treatment-related adverse events were observed in 2.4%, 1.8%, and 1.2% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. Serious adverse events were rare and seldom led to treatment withdrawal with any dose. Treatment-associated myalgia was observed in 1.4%, 1.5%, and 0.7% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. No cases of rhabdomyolysis were reported in any group. Persistent elevations in hepatic transaminases >3 times ULN were observed in 0.1%, 0.6%, and 0.2% of patients in the atorvastatin 10 mg, atorvastatin 80 mg, and placebo groups, respectively. The incidence of treatment-associated adverse events for atorvastatin 80 mg was similar to that of atorvastatin 10 mg and placebo. In conclusion, the results of this analysis support the positive safety profile of atorvastatin at the highest dose.

Lipid and Stroke

1) Amarenco P, Labreuche J, Lavallee P, et al. Statins in stroke prevention and carotid atherosclerosis: systematic review and up-to-date meta-analysis. Stroke 2004; 35:2902-2909.2) Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary prevention of cardiovascular disease with atorvastatin in type 2 diabetes in the Collaborative Atorvastatin Diabetes Study (CARDS): multicentre randomised placebo-controlled trial. Lancet 2004; 364:685-696.3) Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterollowering with simvastatin in 5963 people with diabetes: a randomised placebo-controlled trial. Lancet 2003; 361:2005-2016.4) Sever PS, Dahlof B, Poulter NR, et al. Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial. Lancet 2003; 361:1149-1158.5) Amarenco P, Bogousslavsky J, Callahan AS, et al. Design and baseline characteristics of the stroke prevention by aggressive reduction in cholesterol levels (SPARCL) study. Cerebrovasc Dis 2003; 16:389-395.

The importance of aggressive lipid management in patients at risk: evidence from recent clinical trials.

Clinical trials that evaluate more aggressive cholesterol reduction in a broader range of patients at high risk for coronary heart disease (CHD) are needed to fill gaps in our understanding of the impact of lipid-lowering therapy on risks for clinical events and mortality. This paper briefly reviews results from recent landmark studies that have evaluated the benefits of aggressive lipid-lowering therapy in patients with, or at risk for, CHD. The Reversing Atherosclerosis with Aggressive Lipid Lowering (REVERSAL) study demonstrated that aggressive treatment with atorvastatin was significantly more effective than less aggressive therapy with pravastatin in slowing the progression of atherosclerosis in patients with symptomatic CHD. Results from two large-scale clinical end-point trials, the Heart Protection Study (HPS) and the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA), have shown that aggressive lipid-lowering treatment in patients with relatively low baseline levels of low-density lipoprotein cholesterol (LDL-C) significantly reduces CHD risk. Taken together, the results of these landmark trials not only support aggressive lipid lowering in patients at risk for CHD, but also suggest that greater LDL-C reductions may improve outcomes across a wide range of patients.

Association of dyslipidemia and effects of statins on nonmacrovascular diseases

Background: Statins have mechanisms of action that expand their effects beyond cholesterol lowering and atherosclerotic medical conditions. Objective: This review summarizes clinical evidence for the association of dyslipidemia and the effects of statin use on aortic stenosis, Alzheimer's dementia (AD), osteoporosis, prevention of diabetes mellitus (DM), diabetic retinopathy, age-related macular degeneration, and diabetic/nondiabetic nephropathy. Methods: An English-language literature search was conducted using MEDLINE (1966-June 2003). Bibliographies of retrieved articles were reviewed. Search terms included statin, HMG-CoA reductase inhibitors, aortic stenosis, Alzheimer's dementia, osteoporosis, prevention of diabetis, diabetic retinopathy, age-related macular degeneration, diabetic nephropathy, and nondiabetic nephropathy. Results: Three retrospective cohort trials have shown an association between statin use and the progression of aortic stenosis; one of these trials observed a 45% decrease in aortic valve area in 1 year. In AD, one cross-sectional analysis found 60% to 73% lower AD rates in lovastatin or pravastatin recipients ( P < 0.001). Of the multiple observational studies on the effect of statins on fracture risk, some have shown a decreased risk, with an odds ratio as low as 0.50 (95% CI, 0.33–0.76); others have demonstrated no association. A post hoc analysis of the West of Scotland Coronary Prevention Study found a 30% reduction in the development of DM ( P = 0.042), but this was not duplicated in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm. A small clinical trial of 6 patients (11 eyes) demonstrated improved retinal hard exudates with pravastatin treatment in patients with diabetic retinopathy. In a cross-sectional analysis, age-related macular degeneration was found to be less common among statin users than nonusers (4% [ 1 27 ] vs 22% [ 76 352 ]; P = 0.02. Multiple small clinical trials of 19 to 56 patients with diabetic and nondiabetic nephropathy at various stages generated inconsistent results for an association between statin use and decreased albumin excretion rate and decreased rate of decline in glomerular filtration. Conclusion: Data of variable quantity and quality support the use of statins as adjuncts in the treatment of nonmacrovascular diseases.

Isoprenoid metabolism and the pleiotropic effects of statins.

Convincing evidence from basic research and animal studies shows that 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase inhibitors (ie, statins) exert cardiovascular protective effects beyond cholesterol lowering. Because of the central role of low-density lipoprotein (LDL) cholesterol in mediating vascular pathology and the efficacy of statins for lowering LDL cholesterol, the clinical importance of these additional nonlipid effects remains to be determined. Nevertheless, there is growing evidence from recent clinical trials that suggests that some of the beneficial effects of statins may be unrelated to changes in LDL cholesterol. Indeed, in animal studies many of the cholesterol-independent or pleiotropic effects of statins are due predominantly to inhibition of isoprenoid, but not cholesterol, synthesis. Thus, with the recent findings of the Heart Protection Study and Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm, the potential cholesterol-independent effects of statins have shifted the treatment strategy from numerical lipid parameters to the global assessment of cardiovascular risks.

Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial

Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial

Prevention of coronary and stroke events with atorvastatin in hypertensive patients who have average or lower-than-average cholesterol concentrations, in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm (ASCOT-LLA): a multicentre randomised controlled trial

The lowering of cholesterol concentrations in individuals at high risk of cardiovascular disease improves outcome. No study, however, has assessed benefits of cholesterol lowering in the primary prevention of coronary heart disease (CHD) in hypertensive patients who are not conventionally deemed dyslipidaemic. Of 19342 hypertensive patients (aged 40-79 years with at least three other cardiovascular risk factors) randomised to one of two antihypertensive regimens in the Anglo-Scandinavian Cardiac Outcomes Trial, 10305 with non-fasting total cholesterol concentrations 6.5 mmol/L or less were randomly assigned additional atorvastatin 10 mg or placebo. These patients formed the lipid-lowering arm of the study. We planned follow-up for an average of 5 years, the primary endpoint being non-fatal myocardial infarction and fatal CHD. Data were analysed by intention to treat. Treatment was stopped after a median follow-up of 3.3 years. By that time, 100 primary events had occurred in the atorvastatin group compared with 154 events in the placebo group (hazard ratio 0.64 [95% CI 0.50-0.83], p=0.0005). This benefit emerged in the first year of follow-up. There was no significant heterogeneity among prespecified subgroups. Fatal and non-fatal stroke (89 atorvastatin vs 121 placebo, 0.73 [0.56-0.96], p=0.024), total cardiovascular events (389 vs 486, 0.79 [0.69-0.90], p=0.0005), and total coronary events (178 vs 247, 0.71 [0.59-0.86], p=0.0005) were also significantly lowered. There were 185 deaths in the atorvastatin group and 212 in the placebo group (0.87 [0.71-1.06], p=0.16). Atorvastatin lowered total serum cholesterol by about 1.3 mmol/L compared with placebo at 12 months, and by 1.1 mmol/L after 3 years of follow-up. The reductions in major cardiovascular events with atorvastatin are large, given the short follow-up time. These findings may have implications for future lipid-lowering guidelines.

The anglo-scandinavian cardiac outcomes trial (ASCOT)

Methods: We used data from the randomised, placebo-controlled Anglo-Scandinavian Cardiac Outcomes Trial-Lipid Lowering Arm (ASCOT-LLA) to conduct a prespecified comparison of the lipid-lowering efficacy of statin therapy among hypertensive participants from different ethnic groups in the UK and Ireland. The effects of atorvastatin (10mg daily) and placebo on fasting plasma lipid profiles were compared in matched groups of Whites and Blacks (of African-Caribbean or African origin) and Whites and South Asians (from the Indian subcontinent), adjusting for placebo effect.