Altace - Clinical Pharmacology

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Pharmacodynamics

Single doses of ramipril of 2.5Ð 20 mg produce approximately 60Ð 80% inhibition of ACE activity 4 hours after dosing with approximately 40Ð 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 activ-ity 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, place-bo controlled, 2x2 factorial design, double-blind study conducted in 9,541 patients (4,645 on ALTACE) 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 ALTACE (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 ALTACE (10 mg/ day) significantly reduced the rate of myocardial infarc-tion, 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.

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