Ramipril (Page 2 of 7)

Pharmacodynamics

Single doses of ramipril of 2.5–20 mg produce approximately 60–80% inhibition of ACE activity 4 hours after dosing with approximately 40–60% inhibition after 24 hours. Multiple oral doses of ramipril of 2.0 mg or more cause plasma ACE activity to fall by more than 90% 4 hours after dosing, with over 80% inhibition of ACE activity remaining 24 hours after dosing. The more prolonged effect of even small multiple doses presumably reflects saturation of ACE binding sites by ramiprilat and relatively slow release from those sites.

Pharmacodynamics and Clinical Effects

Reduction in Risk of Myocardial Infarction, Stroke, and Death from Cardiovascular Causes

The Heart Outcomes Prevention Evaluation study (HOPE study) was a large, multi-center, randomized, placebo controlled,2×2 factorial design, double-blind study conducted in 9,541 patients (4,645 on ramipril) who were 55 years or older and considered at high risk of developing a major cardiovascular event because of a history of coronary artery disease, stroke, peripheral vascular disease, or diabetes that was accompanied by at least one other cardiovascular risk factor (hypertension, elevated total cholesterol levels, low HDL levels, cigarette smoking, or documented microalbuminuria). Patients were either normotensive or under treatment with other antihypertensive agents. Patients were excluded if they had clinical heart failure or were known to have a low ejection fraction (<0.40). This study was designed to examine the long-term (mean of five years) effects of ramipril (10 mg orally once a day) on the combined endpoint of myocardial infarction, stroke or death from cardiovascular causes.

The HOPE study results showed that ramipril (10 mg/day) significantly reduced the rate of myocardial infarction, stroke or death from cardiovascular causes (651/4645 vs. 826/4652, relative risk 0.78), as well as the rates of the 3 components of the combined endpoint.

Ramipril Placebo Relative Risk
Outcome (N=4645) (N=4652) (95% CI)
no. (%) P value
Combined End-point
(MI, stroke, or death from CV cause) 651 (14.0%) 826 (17.8%) 0.78 (0.70–0.86), P=0.0001
Component End-point
Death from Cardiovascular Causes 282 (6.1%) 377 (8.1%) 0.74 (0.64–0.87), P=0.0002
Myocardial infarction 459 (9.9%) 570 (12.3%) 0.80 (0.70–0.90), P=0.0003
Stroke 156 (3.4%) 226 (4.9%) 0.68 (0.56–0.84), P=0.0002
Overall Mortality
(Death from any Cause) 482 (10.4%) 569 (12.2%) 0.84 (0.75–0.95), P=0.005

This effect was evident after about one year of treatment.

figure
(click image for full-size original)

Figure 1: Kaplan-Meier Estimates of the composite outcome of MI, Stroke, or Death from CV causes in the Ramipril Group and the Placebo Group. The relative risk of the composite outcomes in the Ramipril Group as compared with the Placebo Group was 0.78% (95% confidence interval, 0.70–0.86).

Ramipril was effective in different demographic subgroups, (i.e., gender, age), subgroups defined by underlying disease (e.g., cardiovascular disease, hypertension), and subgroups defined by concomitant medication. There were insufficient data to determine whether or not ramipril was equally effective in ethnic subgroups.

This study was designed with a prespecified substudy in diabetics with at least one other cardiovascular risk factor. Effects of ramipril on the combined endpoint and its components were similar in diabetics (n=3,577) to those in the overall study population.

RamiprilPlacebo Relative
Outcome (N=1808) (N=1769) Risk Reduction
no. (%) (95% CI)
Combined End-point
(MI, stroke, or death from CV cause) 277 (15.3%) 351 (19.8%) 0.25 (0.12–0.36), P=0.0004
Component End-point
Death from Cardiovascular Causes 112 (6.2%) 172 (9.7%) 0.37 (0.21–0.51), P=0.0001
Myocardial infarction 185 (10.2%) 229 (12.9%) 0.22 (0.06–0.36), P=0.01
Stroke 76 (4.2%) 108 (6.1%) 0.33 (0.10–0.50), P=0.007
figure
(click image for full-size original)

Figure 2: The Beneficial Effect of Treatment with Ramipril on the Composite Outcome of Myocardial Infarction, Stroke, or Death from Cardiovascular Causes Overall and in Various Subgroups. Cerebrovascular disease was defined as stroke or transient ischemic attacks. The size of each symbol is proportional to the number of patients in each group. The dashed line indicates overall relative risk.

The benefits of ramipril were observed among patients who were taking aspirin or other anti-platelet agents, beta-blockers, and lipid-lowering agents as well as diuretics and calcium channel blockers.

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