Augmented Short- and Long-Term Hemodynamic and Hormonal Effects of an Angiotensin Receptor Blocker Added to Angiotensin Converting Enzyme Inhibitor Therapy in Patients With Heart Failure

Background—ACE inhibitors may not adequately suppress deleterious levels of angiotensin II in patients with heart failure. An angiotensin receptor blocker added to an ACE inhibitor may exert additional beneficial effects. Methods and Results—Eighty-three symptomatic stable patients with chronic heart failure receiving long-term ACE inhibitor therapy were randomly assigned to double-blind treatment with valsartan 80 mg BID, valsartan 160 mg BID, or placebo while receiving their usual ACE inhibitor therapy. Studies were performed before and after the first dose of the test drug and again after 4 weeks of therapy. A single dose of lisinopril was administered during study days to ensure sustained ACE inhibition. Compared with placebo, the first dose of valsartan 160 mg resulted in a significantly greater reduction in pulmonary capillary wedge pressure at 3, 4, and 8 hours and during the prespecified 4to 8-hour interval after the dose and in systolic blood pressure at 2, 3, 6, 8, and 12 hours and 4 to 8 hours after the dose. A pressure reduction from valsartan 80 mg did not achieve statistical significance. After 4 weeks of therapy, net reductions in 0-hour trough pulmonary capillary wedge pressure (24.3 mm Hg; P50.16), pulmonary artery diastolic pressure (24.7 mm Hg; P50.013), and systolic blood pressure (26.8 mm Hg; P50.013) were observed in the valsartan 160 mg group compared with placebo. After 4 weeks of therapy, plasma aldosterone was reduced by valsartan 80 mg BID (252.1 pg/mL; P50.001) and 160 mg BID (247.8 pg/mL; P,0.001) compared with placebo, and there was a trend for a reduction in plasma norepinephrine (297 pg/mL; P50.10). Seventy-four of the 83 patients completed the trial. Conclusions—Physiologically active levels of angiotensin II persist during standard long-term ACE inhibitor therapy. (Circulation. 1999;99:2658-2664.)