Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm - ASCOT-LLA

Contribution To Literature:

The ASCOT-LLA trial showed that atorvastatin 10 mg is superior to placebo for primary prevention of CHD in patients with hypertension and CV risk factors.

Description:

The goal of the lipid-lowering limb of the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-LLA) was to determine whether treatment with atorvastatin reduces coronary heart disease (CHD) events in hypertensive patients with relatively low cholesterol levels.

Study Design

Patients Enrolled: 10,305
Mean Follow-Up: Median of 3.3 years
Mean Patient Age: Mean age 63 years
Female: 19%

Patient Populations:

Systolic blood pressure (SBP) ≥160 mm Hg and/or diastolic blood pressure (DBP) ≥100 mm Hg (untreated) or SBP ≥140 mm Hg and/or DBP ≥90 mm Hg (treated); total cholesterol ≤6.5 mmol/L (250 mg/dl) and triglycerides ≤4.5 mmol/L (400 mg/dl); age 40-79 years; ≥3 cardiovascular (CV) disease risk factors; and no history of CHD.

Exclusions:

Previous myocardial infarction (MI), currently treated angina, cerebrovascular event within 3 months, fasting triglycerides >4.5 mmol/L, heart failure, uncontrolled arrhythmias, or any clinically important hematological or biochemical abnormality on routine screening.

Primary Endpoints:

Nonfatal MI and fatal CHD.

Secondary Endpoints:

Primary outcome without silent MI, all-cause mortality, CV mortality, fatal and nonfatal stroke, fatal and nonfatal heart failure, total coronary endpoints, and all CV events and procedures.

Drug/Procedures Used:

Patients in the ASCOT trial (n = 19,342) were randomized open-label to one of the two antihypertensive treatments. Patients with a total cholesterol <6.5 mmol/L were additionally randomized double-blind to either atorvastatin (10 mg; n = 5,168) or placebo (n = 5,137). This summary reports on the results of the atorvastatin versus placebo limb of the trial.

Principal Findings:

Both total cholesterol and low-density lipoprotein cholesterol (LDL-C) at 3-year follow-up were 1.0 mmol/L lower in the atorvastatin arm versus placebo. The lipid-lowering limb of the trial was discontinued early, due to a Data Safety and Monitoring Board recommendation, because of a significant reduction in the primary endpoint of nonfatal MI and fatal CHD (hazard ratio [HR] 0.64, 95% confidence interval [CI] 0.50-0.83, p = 0.0005).

Fatal and nonfatal strokes were also lower in the atorvastatin arm (HR 0.73, 95% CI 0.56-00.96, p = 0.0236), as was the composite of all CV events and procedures (HR 0.79, 95% CI 0.69-0.90, p = 0.0005). All-cause mortality did not differ significantly between the arms (HR 0.87, 95% CI 0.71-1.06, p = 0.1649). With the exception of female gender, all of the prespecified subgroups favored the atorvastatin arm for the primary endpoint, with no heterogeneity in any subgroup.

Subanalysis of side-effects: During the blinded phase, the incidence of important adverse events, including muscle-related (2.03% vs. 2.0%/year, p = 0.72) and erectile dysfunction (1.86% vs. 2.14%/year, p = 0.13), were similar between the atorvastatin and placebo arms; sleep disturbances were lower in the atorvastatin arm (1.0% vs. 1.46%, p = 0.0005). In contrast, during the unblinded phase, nonrandomized phase, muscle-related adverse events were higher in the atorvastatin arm (1.26% vs. 1.0%/year, p = 0.006).

Interpretation:

Among patients with hypertension and relatively low cholesterol, treatment with atorvastatin was associated with a reduction in the primary endpoint of nonfatal MI and fatal CHD at 3-year follow-up. The trial was discontinued early, due to the highly favorable results associated with atorvastatin therapy. The results of a subanalysis, including the unblinded nonrandomized phase, indicate that muscle-related adverse events are not more common with low-dose atorvastatin compared with placebo when blinding is maintained, but are higher when patients are unblinded, suggestive of a possible nocebo effect with statin therapy. This confirms findings from other randomized controlled trials showing no to minimal increase in true drug-related muscle adverse events with statin therapy compared with placebo.

The ALLHAT trial had a similar design, with hypertensive patients randomized to antihypertensive therapy, and a subgroup of patients with mild hypercholesterolemia randomized to pravastatin versus usual care. Unlike the ASCOT trial, no significant benefit was associated with statin therapy in the ALLHAT patients. However, the ASCOT results are in line with other large statin trials such as 4S, CARE, LIPID, and PROSPER, all of which demonstrated a benefit in morbidity and/or mortality with statin therapy.

References:

Gupta A, Thompson D, Whitehouse A, et al., on behalf of the ASCOT Investigators. 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. Lancet 2017;May 2:[Epub ahead of print].

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;361:1149–58.

Presented at Late-Breaking Clinical Trials, ACC 2003.

Presented at the European Society of Cardiology, Vienna, Austria, September 2003.

Clinical Topics: Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Homozygous Familial Hypercholesterolemia, Lipid Metabolism, Nonstatins, Novel Agents, Statins, Hypertension

Keywords: Myocardial Infarction, Stroke, Hydroxymethylglutaryl-CoA Reductase Inhibitors, Diuretics, Coronary Disease, Blood Pressure, Heptanoic Acids, Hypercholesterolemia, Calcium Channel Blockers, Primary Prevention, Pyrroles, Cholesterol, Pravastatin, Triglycerides, Hypertension


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