Despite novel advances in treatmen...

Despite novel advances in treatment, heart failure carries a high risk of morbidity and mortality. About 550000 just discovered cases are diagnosed annually, and approximately 50000 bodys die of heart failure each year. (1)

The treatment goal in patients with heart failure is twofold: to check symptoms and to extend life span. Beta blocker (2) angiotensin-converting enzyme (ACE) inhibitors, (3) and spironolactone (Aldactone) (4) have been shown to decrease mortality. Angiotensin-receptor blocker also have been studied in the treatment of heart failure, and several studies have shown significant symptomatic improvement, similar to that associated with ACE inhibitor therapy. However, angiotensin-receptor blocker do not decrease mortality rates in patients with heart failure. (5)

Because of their different mechanisms of action, ACE inhibitors and angiotensin-receptor blocker are not interchangeable. However, when used in combination, they theoretically may benefit patients with heart failure. This article reviews the literature and available evidence onward the use of ACE inhibitors and angiotensin-receptor blocker in combination for the treatment of patients with congestive heart failure.

Pathophysiology

The renin-angiotensin-aldosterone plan plays an important role in the unfolding and progression of cardiovascular disease. ACE inhibitors and angiotensin-receptor blocker affect the plan at different levels and thus may have an additive event Angiotensinogen, the initial substrate of the renin-angiotensin-aldosterone classification is produced in the liver; renin re-creates it to angiotensin I in the kidneys. ACE regenerates angiotensin I to angiotensin II, a mighty vasoconstrictor with a broad image of activity in target organs. Angiotensin II also stimulates the release of aldosterone, which causes sodium and fluid retention. The actions of angiotensin II are mediated by the agency of receptor A[T.sub.1], which triggers detrimental forces and A[T.sub.2], which triggers any beneficial effects.

Another element of the renin-angiotensin-aldosterone system is bradykinin, a vasoactive peptide metabolized on the same enzyme that change the heart ofs angiotensin I to angiotensin II. The use of ACE inhibitors to arrest the breakdown of bradykinin also furthers vasodilation, natriuresis, and a beneficial weight on cardiac remodeling.

Studies have shown that despite adequate ACE inhibition, angiotensin II flats eventually return to nearly normal evens because the chymase enzymes are an alternate pathway for angiotensin conversion. Angiotensin-receptor blocker work by way of blocking the effects of angiotensin II at the A[T.sub.1] receptor, allowing beneficial drifts at the A[T.sub.2] receptor. When angiotensin-receptor blocker are taken alone, the inactivation of bradykinin move forwards normally, without the beneficial accumulation promot by the agency of ACE inhibitors. The use of an ACE inhibitor in combination with an angiotensin-receptor blocker theoretically could tender benefits by allowing bradykinin to accumulate while blocking the deleterious issues of angiotensin II.

Search Methods

To find relevant patient-oriented research, we searched MEDLINE, InfoRetriever, and our acknowledge files for "angiotensin-receptor blockers" and "ARBs." We limited the research to randomized controll trials (RCTs) that evaluated the part of angiotensin-receptor blockers and ACE inhibitors onward patient-oriented outcomes.

Our literature review place a small number of studies that dealt specifically with the combination of ACE inhibitors and angiotensin-receptor blocker most numerous of the early studies were of short duration and had not many participants. Many of the studies focused solely forward the physiologic effects of therapy.

MORTALITY

Based forward a meta-analysis of six studies involving nearly 6000 patients, the addition of an angiotensin-receptor blocker to ACE inhibitor therapy is not more effective than ACE inhibitor treatment alone in reducing mortality. (5) [Evidence horizontal A, meta-analysis] The largest consideration was the Valsartan Heart Failure Trial (Val-HeFT), (6) a randomized, placebo-controlled trial involving 5010 patients across nearly two years.

Patients in Val-HeFT6 had an ejection fraction of les than 40 percent and a modern York Heart Association (NYHA) classification of II to IV. Patients took an ACE inhibitor (92 percent) and/or diuretic (85 percent) and one patients also took digoxin and beta blocker In addition to this "background therapy," patients received valsartan, in a dosage of 40 mg twice daily, titrated to 160 mg twice daily, or placebo. During the two-year follow-up period, 19 percent of consideration participants died; there was no difference in mortality rates between the angiotensin-receptor-blocker assign places to and the placebo group (relative risk [RR] 102; 95 percent confidence interval [CI], 090 to 115)

A not long ago published study, the Candesartan in Heart Failure: Assessment of Mortality and Morbidity (CHARM)-Added thought (7) has shown similar issues In this study, 2,548 patients with a NYHA classification of II to IV who already were taking an ACE inhibitor were randomized to receive placebo or candesartan up to 32 mg daily. As with the Val-HeFT trial and the meta-analysis, overall death rates were similar with and without candesartan.