Modifying the natural history of atherosclerosis: the SECURE trial.

abstract

Experimental and epidemiological evidence suggests that activation of the reninangiotensin-aldosterone system and oxidative modification of low density lipoprotein cholesterol both play important roles in atherosclerosis. A substudy of the HOPE (Heart Outcomes Prevention Evaluation) trial, the SECURE trial (Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E), evaluated the effects of long-term treatment with the angiotensin-converting enzyme (ACE) inhibitor, ramipril, and with vitamin E on atherosclerosis progression in high risk patients. A total of 732 patients were enrolled into the study. These patients were 55 years or older, had vascular disease or diabetes with at least one other cardiovascular risk factor, but did not have heart failure or low ejection fraction. Patients were randomly assigned according to a three-by-two factorial design to receive placebo, ramipril 2.5 mg/day or ramipril 10 mg/day and placebo or vitamin E 400 IU/day. Progression of atherosclerosis was evaluated by B-mode carotid ultrasonography. The primary outcome evaluated was the annualised progression slope of the mean maximum carotid intimal-medial thickness (IMT) across 12 pre-selected carotid arterial segments. The average follow-up was 4.5 years. The progression slope of the mean maximum IMT was 0.0217 +/- 0.04 mm/year in the placebo group, 0.018 +/- 0.44 mm/year in the ramipril 2.5 mg/day group and 0.0137 +/- 0.04 in the ramipril 10 mg/day group (P = 0.33 for the overall effect of ramipril and P = 0.028 for the comparison between patients receiving ramipril placebo and ramipril 10 mg/day). The reduction in atherosclerotic progression observed with ramipril remained significant after adjusting for systolic and diastolic blood pressure changes (P = 0.043) and after multivariate adjustment (P = 0.046). Administration of vitamin E 400 IU/day had no impact on atherosclerosis progression. The SECURE study is the first demonstration, in human subjects, of an effect of ACE inhibition on atherosclerotic progression. This benefit cannot be explained by the lowering of blood pressure alone. Vitamin E 400 IU/day had a neutral effect on the ultrasound measurements of atherosclerosis progression in the SECURE trial.