Introduction

Diuretics, digoxin, ACE inhibitors and beta-blockers are the main medical therapies 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 significantly improved clinical signs and symptoms with reduction in hospitalization but did not improve overall mortality.

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 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 depending on blood pressure values and renal function. For instance, 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 were reasons not to increase the dose of valsartan.

The primary outcome of the trial focused on combined morbidity and mortality as well as 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. However, 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 heart function as measure by ejection fraction, functional 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, and on severity of heart failure. However, benefits apparently seemed dependent on background therapy. Indeed, patients who were treated with both ACE inhibitors and beta-blockers (representing one third of the population studied) were 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 with less clinical symptoms attributable to heart failure. Quality of life also improved in those where it could be assessed. There was no evidence of an overall improvement in mortality.

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 antagonist in those patients already receiving combined therapy of ACE inhibitors and beta blockers.