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Implications of ASCOT and CARDS
Christie M. Ballantyne, MD
Clinical trial evidence has established the benefit of lipid-regulating statin therapy in patients with elevated low-density lipoprotein cholesterol (LDL-C), but in a growing number of patients, cardiovascular risk is increased by the presence of the metabolic syndrome, characterized by elevated triglycerides, low high-density lipoprotein cholesterol (HDL-C), hypertension, and insulin resistance. While determining the optimal therapy to reduce cardiovascular risk in patients with the metabolic syndrome will require large clinical trials that specifically enroll this high-risk population, the results of 2 recent clinical trials can provide insight into evaluating treatments until specially designed trials are available.
Anglo-Scandinavian Cardiac Outcomes Trial
The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)1 compared 2 antihypertensive treatment regimens in patients without known coronary artery disease (CAD) who had hypertension plus at least 3 other cardiovascular risk factors (smoking, left ventricular hypertrophy, ECG abnormalities, history of early CAD in a first-degree relative, age 55 years or older, microalbuminuria/proteinuria, type 2 diabetes mellitus (DM), peripheral vascular disease, history of a cerebrovascular event, male sex, total cholesterol/HDL-C ratio of 6 or higher). In the lipid-lowering arm of the study (ASCOT-LLA),2 the subset of patients with total cholesterol levels of 250 mg/dL or less were also randomized to receive atorvastatin 10 mg/d or placebo. Although the planned follow-up was 5 years (or until a specified number of end points had occurred), both the lipid-lowering and the blood pressure–lowering arms were stopped early because of clear clinical benefit.2,3
In ASCOT-LLA (n=10,305), which was stopped at a median follow-up of 3 years because of clear benefit with respect to the primary end point of nonfatal myocardial infarction (MI) or CAD death, mean LDL-C levels were reduced from 131 mg/dL at baseline to 88 mg/dL at 3 years with atorvastatin, and the primary end point was significantly reduced by 36%. Significant benefits with respect to secondary end points included a 27% reduction in fatal and nonfatal stroke, a 21% reduction in total cardiovascular events, and a 29% reduction in total coronary events. In post hoc analyses, similar benefit with respect to the primary end point was observed regardless of total cholesterol levels at baseline.2
The results of ASCOT-LLA and other recent statin trials led to an update to the third Adult Treatment Panel (ATP III) guidelines of the US National Cholesterol Education Program, which had not previously recommended the use of lipid-lowering drug therapy for primary prevention in patients whose LDL-C level was <130 mg/dL.4 Because many patients in ASCOT had LDL-C levels of <130 mg/dL yet received benefit with atorvastatin, the updated guidelines recommend the consideration of lipid-lowering drug therapy for patients at moderately high risk whose LDL-C level is 100-129 mg/dL, with an optional LDL-C goal of <100 mg/dL. Although the patients in ASCOT did not have known CAD or substantially elevated LDL-C, they were at increased risk because of hypertension and other cardiovascular risk factors, and for this reason, the results of the trial support the use of global risk assessment in determining the need for and intensity of therapy.
The blood pressure–lowering arm of ASCOT (ASCOT-BPLA; n=19,257)3 used a prospective, randomized, open, blinded end point (PROBE) design to compare 2 antihypertensive treatment regimens: amlodipine (a calcium channel blocker) with or without perindopril (an angiotensin-converting enzyme [ACE] inhibitor) versus atenolol (a b-blocker) with or without bendroflumethiazide (a thiazide diuretic); if the target blood pressure of <140/90 mm Hg (<130/80 mm Hg in patients with DM) was not achieved with prespecified dose increases, sustained-release doxazosin (an a-blocker) was added to the randomized treatment. ASCOT-BPLA was stopped early because of clear benefit with respect to the secondary end point of total mortality, but before the prespecified number of primary end point events had occurred (median follow-up 5.4 years). Preliminary data indicated that the primary end point of nonfatal MI or CAD death was reduced by approximately 10% with amlodipine/perindopril compared with atenolol/bendroflumethiazide, but the difference was not statistically significant, in part, probably, because stopping the study early reduced the statistical power to test the primary hypothesis. However, significant benefit was observed with amlodipine/perindopril with respect to the secondary end points of total mortality (~15% reduction), all coronary events (~15%), fatal and nonfatal stroke (~25%), and cardiovascular mortality (~25%). In addition, in patients randomized to the regimen of amlodipine, ACE inhibitor, and a-blocker, blood levels of HDL-C were found to be 4.5 mg/dL higher, triglyceride levels were 25 mg/dL lower, and the incidence of new-onset DM was reduced by approximately 30% compared with the b-blocker–based regimen. Although the mean difference in blood pressure between the 2 treatment regimens was 2.9/1.8 mm Hg over the course of the study, with lower levels obtained with amlodipine/perindopril, by the end of the study blood pressure was the same with both treatment regimens, suggesting that the differences in clinical events end points were for the most part not due to differences in blood pressure.3
Collaborative Atorvastatin Diabetes Study
The Collaborative Atorvastatin Diabetes Study (CARDS)6 compared the effects of atorvastatin 10 mg/d and placebo on clinical events in patients with type 2 DM, LDL-C levels of 160 mg/dL or less, fasting triglyceride levels of 600 mg/dL or less, and at least 1 other risk factor (hypertension, retinopathy, microalbuminuria or macroalbuminuria, current smoking) but without previous CAD events, cerebrovascular accident, or severe peripheral vascular disease. CARDS was stopped 2 years early because of a significant difference between treatment groups.
At a median follow-up of 5.4 years, the primary end point (first CAD event [MI including silent infarction, unstable angina, CAD death, resuscitated cardiac arrest], revascularization, or stroke) was significantly reduced by 37% with atorvastatin compared with placebo; the risk reduction was similar whether baseline LDL-C was above or below the median level of 120 mg/dL. LDL-C was reduced from 118 mg/dL at baseline to 82 mg/dL at 4 years with atorvastatin, a mean 40% reduction for the duration of the study; triglycerides were reduced by a mean of 19% from baseline, but HDL-C was not significantly changed.
Implications of ASCOT and CARDS
Insulin resistance, with associated hypertension and atherogenic dyslipidemia (low HDL-C and elevated triglycerides), may be viewed as a spectrum, ranging from the metabolic syndrome to the more severe manifestation of diabetes. The results of ASCOT and CARDS suggest that statin therapy provides clinical benefit across this spectrum of insulin resistance, as well as across the range of LDL-C levels included in these studies. The initial results of ASCOT-BPLA also suggest that the choice of an antihypertensive regimen that improves not only blood pressure but also, potentially, insulin sensitivity and HDL-C/triglycerides provides greater benefit in patients with these metabolic abnormalities.
References
1. Sever PS, Dahlöf B, Poulter NR, et al, for the ASCOT investigators. Rationale, design, methods and baseline demography of participants of the Anglo-Scandinavian Cardiac Outcomes Trial. J Hypertens. 2001;19:1139-1147.
2. Sever PS, Dahlöf B, Poulter NR, et al, for the ASCOT Investigators. 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.
3. Sever PS. The Anglo-Scandinavian Cardiac Outcomes Trial: morbidity–mortality outcomes in the blood pressure–lowering arm of the trial (ASCOT-BPLA). Presented at the American College of Cardiology 54th Annual Scientific Session; March 8, 2005; Orlando, Florida.
4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497.
5. Grundy SM, Cleeman JI, Bairey Merz CN, et al, for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III guidelines. Circulation. 2004;110:227-239.
6. Colhoun HM, Betteridge DJ, Durrington PN, et al, on behalf of the CARDS Investigators. 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.
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