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

Abstract

for the Vasodilator Heart Failure Trial (V-HeFT) Study Group* Background-ACE inhibitors may not adequately suppress deleterious levels of angiotensin II in patients with heartfailure. 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 4-to 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 (Ϫ4.3 mm Hg; Pϭ0.16), pulmonary artery diastolic pressure (Ϫ4.7 mm Hg; Pϭ0.013), and systolic blood pressure (Ϫ6.8 mm Hg; Pϭ0.013) 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 (Ϫ52.1 pg/mL; Pϭ0.001) and 160 mg BID (Ϫ47.8 pg/mL; PϽ0.001) compared with placebo, and there was a trend for a reduction in plasma norepinephrine (Ϫ97 pg/mL; Pϭ0.10). Seventy-four of the 83 patients completed the trial. Conclusions-Physiologically active levels of angiotensin II persist during standard long-term ACE inhibitor therapy.

Combined Blockade of the Renin-Angiotensin System With Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Type 1 Receptor Antagonists

“…In patients with stable CHF, small studies have shown that combined RAS blockade provided greater benefit than singlesite blockade on surrogate end points such as improvement in cardiac load and function, 44 increase in exercise capacity, 45 prevention of LV remodeling, and reduction of neurohormonal activation. 35 All these clinical studies share the same limitations: short treatment periods, small group sizes, administration of a nonstandardized ACE inhibitor treatment that was not at a predetermined maximal dose, and the use of a single fixed dose of an AT1R antagonist.…”

Angiotensin Receptor Blocker Therapy for Heart Failure Patients: Is Combination Treatment a Feasible Prospect?

“…The addition of an ARB to ACEI therapy for heart failure has been shown to have improved neurohormonal, hemodynamic, and left ventricular remodeling effects. 16,17 However, the Valsartan Heart Failure Trial (Val-Heft) reported no difference in mortality outcomes with the combined use of the ARB valsartan with the ACEI captopril compared to ACEI or ARB alone. 26 The rate of adverse events requiring drug discontinuation was significantly higher in the combination drug group than ACEI or ARB group alone; almost half of all patients required a dose reduction and approximately one-quarter required permanent cessation of combination therapy.…”

“…Reports suggest favorable effects on hemodynamic parameters, left ventricular remodeling, and neurohormonal activity in patients with chronic heart failure. 16,17 Concerns have been raised however as to whether combination therapy, particularly with the addition of ARB to ACEI, β-blocker, and aldosterone antagonist is associated with excessive neuroendocrine inhibition. 18 -20 The Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM)-Added trial demonstrated improved clinical outcomes in heart failure patients on combination therapy.…”

Adição de Bloqueador do receptor de angiotensina II na insuficiência cardíaca descompensada

“…Baruch and cols. found a decrease in the pulmonary capillary pressure and a tendency toward a decrease in the peripheral vascular resistance 6 to 12 hours after the administration of valsartan in patients without ACEI 11 . The hemodynamic improvement occurs two hours after the ingestion of losartan, with an 18% decrease in the peripheral vascular resistance and a 25% increase in the cardiac index 12 .…”