INTRODUCTION: Among individuals with a history of myocardial infarction (MI), higher levels of blood pressure (BP) are associated with increased long-term risks of death from coronary heart disease. Treatment with a BP-lowering regimen, based on omapatrilat may result in greater clinical benefits than treatment with a regimen based on a regular angiotensin-converting enzyme (ACE) inhibitor because of more favourable effects on the renin-angiotensin-aldosterone system. METHODS: Seven hundred and twenty-three clinically stable patients with a history of MI or unstable angina, and a mean entry BP of 134/77 mmHg, were randomised to six months treatment with omapatrilat 40 mg, omapatrilat 20 mg, or matching placebo. RESULTS: After six months, mean BP levels (systolic/diastolic) in the omapatrilat 40 mg group were reduced by 4.3/2.9 mmHg (95% confidence interval 1.3 to 7.2/1.2 to 4.6). Mean BP levels in the omapatrilat 20 mg group were reduced by 4.6/1.0 mmHg (1.6 to 7.6/ 0.7 to 2.6) in comparison with the placebo group. Both doses of omapatrilat also produced significant decreases in plasma ACE activity and significant increases in levels of plasma renin activity, atrial natriuretic peptide, endothelin and homocysteine (p<0.05 for all). Premature discontinuations were more frequent with omapatrilat than with placebo (p<0.001 for 20 mg and 40 mg). CONCLUSIONS: Omapatrilat produced changes in BP, neurohormone and biochemical parameters that were similar for the two doses. The long-term clinical implications of the observed effects are uncertain and a large-scale randomised trial would be required to reliably establish the effects of omapatrilat on the risks of major vascular disease events among patients with coronary heart disease.