Introduction

Diuretics, digoxin, ACE inhibitors and beta-blockers are the cornerstone of pharmacotherapy for patients suffering from heart failure. A recently published international clinical trial conducted with more than 5000 patients concluded that addition of valsartan to the existing treatment did not improve overall mortality but significantly improved clinical signs and symptoms with reduction in hospitalization.

Methods

The Valsartan Heart Failure Trial (Val-HeFT) included 5010 heart failure patients, the majority of whom were in New York Heart Association (NYHA) class II and III (62% and 36%, respectively). Mean base line ejection fraction was only 27%.
A quarter of the patients were diabetics and the majority (57%) had coronary heart disease.

Ninety-three percent of the patients were on ACE-inhibitors, 86% on diuretics, 67% on digoxin and 35% on beta-blockers. Mean age of the patients was 63 years with a majority (80%) of males. Approximately half of the patients (2511) were allocated to receive valsartan while the 2499 remaining ones were given a placebo.

Dose of valsartan were to be doubled every two weeks from a starting daily dose of 40 mg twice daily up to 160 mg twice daily only if the following did not occur: a standing systolic blood pressure below 90 mm Hg, symptoms of hypotension and a serum creatinine concentration of 2.0 mg per deciliter (177µmol per liter) or higher, or an increase of more than 50% of the base line serum creatinine concentration.

The outcomes of primary interest were the combined mortality and morbidity that included cardiac arrest with resuscitation, or hospitalization for heart failure. Administration for 4 hours or more of intravenous drugs to improve heart function outside hospital was also included in the morbidity list criteria. The Minnesota Living with Heart Failure questionnaire was administered to 60 % of the patients.

Results

Overall mortality and mortality due to sudden death or heart failure was similar in valsartan and placebo patients, but the combined mortality and morbidity outcome was significantly in favor of valsartan with a relative risk decline of 13 %. In particular, there was a 24% relative risk reduction of hospitalizations for worsening of heart failure as a first event in valsartan patients in comparison to placebo patients. Patients receiving valsartan also had a better mean improvement in ejection fraction, NYHA classification and clinical signs, such as fatigue, dyspnea, edema and rales. Quality of life deteriorated in the placebo patients but did not change in the valsartan group.

The benefits of valsartan did not depend on age, sex, diagnosis of diabetes or coronary heart disease or NYHA class II or III, but based on post hoc analysis, they were apparently dependent on background therapy. Indeed, patients who were treated with both ACE inhibitors and beta-blockers (representing one third of the population studied) were apparently at increased risk of mortality. By contrast, those receiving ACE inhibitors alone, or beta blockers alone and those receiving none of these two apparently had most benefit of additional angiotensin II inhibition.

Valsartan therapy was well tolerated, with 9.9% of patients discontinuing treatment because of adverse events. This compared with 7.2 % in the placebo group. Reasons for discontinuations were dizziness, hypotension and renal impairment.

Conclusions

Addition of valsartan to the existing medical therapy of patients with heart failure decreases morbidity with less hospitalization because of heart failure and less clinical symptoms. There was no evidence of an improved mortality in the valsartan group in comparison to the placebo group.

The results of this large investigation in patients with NYHA type II and III heart failure however do not support use of additional angiotensin II receptor antagonists in those patients already receiving combined treatment of ACE inhibitors and beta blockers.