Effects of Ramipril and Vitamin E on Atherosclerosis

Abstract

for the SECURE InvestigatorsBackground-Activation of the renin-angiotensin-aldosterone system and oxidative modification of LDL cholesterol play important roles in atherosclerosis. The Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a substudy of the Heart Outcomes Prevention Evaluation (HOPE) trial, was a prospective, double-blind, 3ϫ2 factorial design trial that evaluated the effects of long-term treatment with the angiotensin-converting enzyme inhibitor ramipril and vitamin E on atherosclerosis progression in high-risk patients. Methods and Results-A total of 732 patients Ն55 years of age who had vascular disease or diabetes and at least one other risk factor and who did not have heart failure or a low left ventricular ejection fraction were randomly assigned to receive ramipril 2.5 mg/d or 10 mg/d and vitamin E (RRR-␣-tocopheryl acetate) 400 IU/d or their matching placebos. Average follow-up was 4.5 years. Atherosclerosis progression was evaluated by B-mode carotid ultrasound. The progression slope of the mean maximum carotid intimal medial thickness was 0.0217 mm/year in the placebo group, 0.0180 mm/year in the ramipril 2.5 mg/d group, and 0.0137 mm/year in the ramipril 10 mg/d group (Pϭ0.033). There were no differences in atherosclerosis progression rates between patients on vitamin E and those on placebo. Conclusions-Long-term treatment with ramipril had a beneficial effect on atherosclerosis progression. Vitamin E had a neutral effect on atherosclerosis progression.

Modulating atherosclerosis through inhibition or blockade of angiotensin

“…There was no difference in atherosclerosis progression rates, as measured, between the vitamin E and the placebo-treated groups. 12 This finding is an important contrast to previous evidence suggesting that use of an antioxidant agent might be an effective means of reducing excessive LDL cholesterol oxidation. It is likely that vitamin E therapy is limited to scavenging lipid-soluble oxidants, whereas ACE inhibition blocks vascular superoxide production at its source.…”

“…10,11 In the Study to Evaluate Carotid Ultrasound changes in patients treated with Ramipril and vitamin E (SECURE), a HOPE substudy, ACE inhibition, but not treatment with the antioxidant vitamin E, prevented the progression of atherosclerosis, as measured by the intimal-to-medial ratio of the carotid artery. 12 This is an important contrast to previous findings that suggested that use of an antioxidant vitamin might mitigate atherosclerosis by reducing excessive low-density lipoprotein (LDL) cholesterol oxidation. A brief overview of the role of ACE inhibitors and ARBs in lessening oxidative stress in the vascular system follows.…”

“…Participants (n = 732) were randomly assigned to receive either ramipril 2.5 or 10 mg per day and vitamin E or their matching placebos over an average followup of 4.5 years. 12 Atherosclerosis progression, measured using carotid ultrasound/carotid intimal-to-medial thickness, was significantly less in the ramipril 10 mg versus the placebo-treated patients (p = 0.03). Although there was a trend toward slower progression in the ramipril 2.5 mg group, the difference did not achieve statistical significance.…”

“…This finding from the SECURE substudy is detailed below. 10,12 MICRO-HOPE Substudy: This substudy sought to determine whether ACE inhibition would lower risk factors for CV and renal disease in persons with diabetes. Criteria matched the HOPE trial, and MICRO-HOPE participants (n = 3,577) could also not have clinical proteinuria.…”

Evolving targets for risk reduction in diabetes

“…12 Among the 3,577 subjects with diabetes, those treated with ramipril (compared with placebo) for 4.5 years had a lower risk of death by 24%, myocardial infarction by 22%, and stroke by 33%. In the Study to Evaluate Carotid Ultrasound Changes in Patients Treated with Ramipril and Vitamin E (SECURE), 13 a HOPE substudy, ramipril led to dose-dependent decreases in carotid artery atherosclerosis progression as measured by B-mode ultrasonography. The Losartan Intervention For Endpoint reduction in hypertension study (LIFE) demonstrated superior effectiveness of the angiotensin receptor blocker (ARB) losartan over the beta blocker atenolol with regard to cardiovascular outcomes 14 in the subgroup of patients with diabetes, hypertension, and left ventricular hypertrophy.…”