Cardiac Outcomes Trial-Lipid Lowering Arm 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.

Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase

In blinded randomised controlled trials, statin therapy has been associated with few adverse events (AEs). By contrast, in observational studies, larger increases in many different AEs have been reported than in blinded trials. In the Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial, patients aged 40-79 years with hypertension, at least three other cardiovascular risk factors, and fasting total cholesterol concentrations of 6·5 mmol/L or lower, and who were not taking a statin or fibrate, had no history of myocardial infarction, and were not being treated for angina were randomly assigned to atorvastatin 10 mg daily or matching placebo in a randomised double-blind placebo-controlled phase. In a subsequent non-randomised non-blind extension phase (initiated because of early termination of the trial because efficacy of atorvastatin was shown), all patients were offered atorvastatin 10 mg daily open label. We classified AEs using the Medical Dictionary for Regulatory Activities. We blindly adjudicated all reports of four prespecified AEs of interest-muscle-related, erectile dysfunction, sleep disturbance, and cognitive impairment-and analysed all remaining AEs grouped by system organ class. Rates of AEs are given as percentages per annum. The blinded randomised phase was done between February, 1998, and December, 2002; we included 101 80 patients in this analysis (5101 [50%] in the atorvastatin group and 5079 [50%] in the placebo group), with a median follow-up of 3·3 years (IQR 2·7-3·7). The non-blinded non-randomised phase was done between December, 2002, and June, 2005; we included 9899 patients in this analysis (6409 [65%] atorvastatin users and 3490 [35%] non-users), with a median follow-up of 2·3 years (2·2-2·4). During the blinded phase, muscle-related AEs (298 [2·03% per annum] vs 283 [2·00% per annum]; hazard ratio 1·03 [95% CI 0·88-1·21]; p=0·72) and erectile dysfunction (272 [1·86% per annum] vs 302 [2·14% per annum]; 0·88 [0·75-1·04]; p=0·13) were reported at a similar rate by participants randomly assigned to atorvastatin or placebo. The rate of reports of sleep disturbance was significantly lower among participants assigned atorvastatin than assigned placebo (149 [1·00% per annum] vs 210 [1·46% per annum]; 0·69 [0·56-0·85]; p=0·0005). Too few cases of cognitive impairment were reported for a statistically reliable analysis (31 [0·20% per annum] vs 32 [0·22% per annum]; 0·94 [0·57-1·54]; p=0·81). We observed no significant differences in the rates of all other reported AEs, with the exception of an excess of renal and urinary AEs among patients assigned atorvastatin (481 [1·87%] per annum vs 392 [1·51%] per annum; 1·23 [1·08-1·41]; p=0·002). By contrast, during the non-blinded non-randomised phase, muscle-related AEs were reported at a significantly higher rate by participants taking statins than by those who were not (161 [1·26% per annum] vs 124 [1·00% per annum]; 1·41 [1·10-1·79]; p=0·006). We noted no significant differences between statin users and non-users in the rates of other AEs, with the exception of musculoskeletal and connective tissue disorders (992 [8·69% per annum] vs 831 [7·45% per annum]; 1·17 [1·06-1·29]; p=0·001) and blood and lymphatic system disorders (114 [0·88% per annum] vs 80 [0·64% per annum]; 1·40 [1·04-1·88]; p=0·03), which were reported more commonly by statin users than by non-users. These analyses illustrate the so-called nocebo effect, with an excess rate of muscle-related AE reports only when patients and their doctors were aware that statin therapy was being used and not when its use was blinded. These results will help assure both physicians and patients that most AEs associated with statins are not causally related to use of the drug and should help counter the adverse effect on public health of exaggerated claims about statin-related side-effects. Pfizer, Servier Research Group, and Leo Laboratories.

Polygenic Risk Score Identifies Subgroup With Higher Burden of Atherosclerosis and Greater Relative Benefit From Statin Therapy in the Primary Prevention Setting.

Relative risk reduction with statin therapy has been consistent across nearly all subgroups studied to date. However, in analyses of 2 randomized controlled primary prevention trials (ASCOT [Anglo-Scandinavian Cardiac Outcomes Trial-Lipid-Lowering Arm] and JUPITER [Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin]), statin therapy led to a greater relative risk reduction among a subgroup at high genetic risk. Here, we aimed to confirm this observation in a third primary prevention randomized controlled trial. In addition, we assessed whether those at high genetic risk had a greater burden of subclinical coronary atherosclerosis. We studied participants from a randomized controlled trial of primary prevention with statin therapy (WOSCOPS [West of Scotland Coronary Prevention Study]; n=4910) and 2 observational cohort studies (CARDIA [Coronary Artery Risk Development in Young Adults] and BioImage; n=1154 and 4392, respectively). For each participant, we calculated a polygenic risk score derived from up to 57 common DNA sequence variants previously associated with coronary heart disease. We compared the relative efficacy of statin therapy in those at high genetic risk (top quintile of polygenic risk score) versus all others (WOSCOPS), as well as the association between the polygenic risk score and coronary artery calcification (CARDIA) and carotid artery plaque burden (BioImage). Among WOSCOPS trial participants at high genetic risk, statin therapy was associated with a relative risk reduction of 44% (95% confidence interval [CI], 22-60; P<0.001), whereas in all others, the relative risk reduction was 24% (95% CI, 8-37; P=0.004) despite similar low-density lipoprotein cholesterol lowering. In a study-level meta-analysis across the WOSCOPS, ASCOT, and JUPITER primary prevention, relative risk reduction in those at high genetic risk was 46% versus 26% in all others (P for heterogeneity=0.05). Across all 3 studies, the absolute risk reduction with statin therapy was 3.6% (95% CI, 2.0-5.1) among those in the high genetic risk group and 1.3% (95% CI, 0.6-1.9) in all others. Each 1-SD increase in the polygenic risk score was associated with 1.32-fold (95% CI, 1.04-1.68) greater likelihood of having coronary artery calcification and 9.7% higher (95% CI, 2.2-17.8) burden of carotid plaque. Those at high genetic risk have a greater burden of subclinical atherosclerosis and derive greater relative and absolute benefit from statin therapy to prevent a first coronary heart disease event. URL: http://www.clinicaltrials.gov. Unique identifiers: NCT00738725 (BioImage) and NCT00005130 (CARDIA). WOSCOPS was carried out and completed before the requirement for clinical trial registration.

Evaluation of C-Reactive Protein Before and On-Treatment as a Predictor of Benefit of Atorvastatin: A Cohort Analysis From the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm

The aim of this study was to determine whether baseline and on-statin C-reactive protein (CRP) are independent predictors of cardiovascular (CV) outcome beyond low-density lipoprotein cholesterol (LDL-C). Use of CRP as a predictor of statin treatment remains controversial. We investigated the relationship of baseline and on-treatment CRP with subsequent CV events in Cox models using a subset of white subjects with no history of CV disease from the UK ASCOT (Anglo-Scandinavian Cardiac Outcomes Trial). During 5.5 years of follow-up, a total of 488 subjects experienced a CV event. CV risk increased with baseline CRP (hazard ratio [HR] per 1 SD: 1.21; 95% confidence interval [CI]: 1.09 to 1.33) in an adjusted model. In ASCOT Lipid-Lowering Arm, the relative statin effect in preventing CV events did not differ according to tertiles of baseline CRP (p= 0.69). After 6 months of atorvastatin therapy, the median LDL-C and CRP were reduced by 38.7% and 25.8%, respectively. Those who achieved LDL-C below the median had a reduced CV risk (HR: 0.58; 95% CI: 0.34 to 0.97) compared with those who did not. In contrast, those who achieved a CRP level below the median did not have a reduced risk of CV events (HR: 0.95; 95% CI: 0.59 to 1.55). Among those who achieved LDL-C below the median, there was no difference in CV risk whether they also achieved a CRP level below (HR: 0.55; 95% CI: 0.30 to 1.02) or above the median (HR: 0.56; 95% CI: 0.30 to 1.03). In these primary prevention patients, although baseline CRP independently predicted CV event risk, the achieved CRP level on while statin therapy did not predict CV events, either alone or in combination with LDL-C.

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.

ASCOT-LLA: Statin Legacy Felt with Reduced Non-CV Death Eight Years after Trial End?

Prior treatment with atorvastatin is associated with a reduction in the risk of all-cause mortality compared with placebo 8 years after the early termination of the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm [ASCOT-LLA] and 11 years after initial randomization, according to new findings from a long-term follow-up study.

Impact of atorvastatin among older and younger patients in the Anglo-Scandinavian Cardiac Outcomes Trial Lipid-Lowering Arm

Older patients experience higher rates of cardiovascular disease than younger patients, but may be undertreated with statins due to doubts about efficacy and safety. The Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Trial allowed an evaluation of the efficacy and safety of atorvastatin among older (≥ 65 years) and younger (<65 years) patients with hypertension. A total of 10 305 patients with hypertension, at least three other cardiovascular risk factors, total cholesterol concentrations of 251 mg/dl or less, and no known coronary heart disease (CHD) were randomized to receive atorvastatin 10 mg or placebo. The primary endpoint was a composite of nonfatal myocardial infarction and fatal CHD. There were 4445 patients in the older group (mean 71 years) and 5860 patients (mean 57 years) in the younger group. Among those taking placebo, the older group experienced a higher rate of primary endpoints than the younger group (11.7 vs. 7.6 events per 1000 patient years, respectively). After a median follow-up of 3.3 years, the primary endpoint was reduced by a similar proportion in both older and younger patients (37 vs. 33%, respectively). Although older patients reported more serious adverse events than younger patients, there were no significant differences between atorvastatin and placebo within each age group. Atorvastatin reduced the risk of major cardiovascular events to a similar relative extent in both older and younger patients with treated hypertension. However, given that event rates were higher in older patients, the absolute benefits of atorvastatin were greater for older than younger patients.

The Clinical and Economic Burden of Nonadherence with Antihypertensive and Lipid-Lowering Therapy in Hypertensive Patients

ObjectiveWe sought to determine lifetime costs, morbidity, and mortality associated with varying adherence to antihypertensive and 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statin) therapy in a hypertensive population. MethodsA model was constructed to compare costs and outcomes under three adherence scenarios: no treatment, ideal adherence, and real-world adherence. Simulated patients’ characteristics matched those of participants in the Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm and event probabilities were calculated with Framingham Heart Study risk equations. The real-world adherence scenario employed adherence data from an observational study of a US population; risk reductions at each level of adherence were based on linear extrapolations from clinical trials. Outputs included life expectancy, frequencies of primary and secondary coronary heart disease and stroke, and direct medical costs in 2006 US$. The incremental cost per life-year gained and incremental cost per event avoided were calculated comparing the three adherence scenarios. ResultsMean life expectancy was 14.73 years (no-treatment scenario), 15.07 (real-world adherence), and 15.49 (ideal adherence). The average number of cardiovascular events per patients was 0.738 (no treatment), 0.610 (real-world adherence), and 0.441 (ideal adherence). The incremental cost of real-world adherence versus no treatment is $30,585 per life-year gained, and ideal adherence versus real-world adherence is $22,121 per life-year gained. ConclusionsHypertensive patients taking antihypertensive and statin therapy at real-world adherence levels can be expected to receive approximately 50% of the potential benefit seen in clinical trials. Depending on its cost, the incremental benefits of an effective adherence intervention program could make it an attractive value.

“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?

Statin therapy for prevention of coronary artery disease. The earlier the better or the longer the better?

Cholesterol lowering with statin therapy has been shown to reduce cardiovascular events in a variety of patient categories, ranging from patients with established cardiovascular disease to high-risk individuals with no previous history.1 The degree of benefit relates primarily to a patient's absolute risk of cardiovascular events and to the absolute reduction in low-density lipoprotein (LDL)-cholesterol. The optimal intensity of lipid-lowering therapy has been the focus of recent clinical trials, with growing support in the cardiovascular community for the concept of ‘the lower the better’ for LDL-cholesterol. As a result, the target for LDL-cholesterol has been adjusted for patients at moderate or high risk of cardiovascular events.2 Prolonged statin treatment with a significant reduction in LDL-cholesterol has also been strongly recommended.1 Sever and colleagues have presented the results of a 2-year extension of the Anglo-Scandinavian Cardiac Outcomes Trial lipid-lowering arm (ASCOT-LLA Extension).3 In the initial ASCOT trial, the blood pressure-lowering arm (ASCOT-BPLA) compared the effect of two different antihypertensive regimens on cardiovascular outcomes. ASCOT-LLA … *Corresponding author. Tel: +47 2307 1246, Fax: +47 2307 1247. Email : Hallvard.Holdaas{at}rikshospitalet.no

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.

Reduction in Cardiovascular Events With Atorvastatin in 2,532 Patients With Type 2 Diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)

Reduction in Cardiovascular Events With Atorvastatin in 2,532 Patients With Type 2 Diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)

Reduction in Cardiovascular Events With Atorvastatin in 2,532 Patients With Type 2 Diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)

Reduction in Cardiovascular Events With Atorvastatin in 2,532 Patients With Type 2 Diabetes: Anglo-Scandinavian Cardiac Outcomes Trial–Lipid-Lowering Arm (ASCOT-LLA)