Authors
Cohn J and Togononi G for The Val-HeFT Investigators
Title
A randomized trial of the angiotensin-receptor blocker valsartan in chronic heart failure.
References
N Engl J Med 2001;345:1667-75.
Background
Heart failure continues to cause high rates of mortality and hospitalizations despite ACE inhibitor (ACEi) and β-blockers therapy. Further inhibition of angiotensin II by angiotensin-receptor blockers (ARBs) such as valsartan may provide further protection.
Purpose
To determine whether valsartan, when added to optimal therapy including ACEi positively affects survival rates and clinical outcomes in patients with systolic heart failure and NYHA Class II – IV symptoms.
Design
  • Randomized, double-blind, placebo-controlled trial
  • 5010 patients ≥18 years with HF for ≥3 months, stable NYHA class II, III or IV symptoms and receiving optimal pharmacotherapy for >2 weeks (ACE inhibitors, diuretics, digoxin and beta-blockers)
  • LVEF ≤40% and dilated LV
Exclusion Criteria
  • Pregnancy, nursing mothers, or women of child-bearing potential not using contraception, postpartum cardiomyopathy
  • hemodynamically significant valvular disease, hypertrophic cardiomyopathy, cor pulmonale, decompensated HF, ACS, CAD likely requiring intervention, prior or planned heart transplant
  • Within past 3 months: MI, stroke, cardiac surgery, PCTA, sustained VT with syncope, treatment with class 1C agents, IV inotropes or vasodilators, or AII antagonists
  • serum creatinine >221 µmol/L, hepatic failure, hematologic disorder
  • Malignancies limiting 5 year survival, <5 year life expectancy
  • Contraindication to ARBs, prior double-blind treatment in a valsartan CHF trial, any investigational drug trial within 30 days, noncompliance
Follow-Up
Average 23 months (0-38 months)
Treatment Regimen
  • Valsartan 40 mg twice daily, then dose doubled every two weeks to target dose of 160 mg twice daily vs. placebo (randomization was stratified to beta-blocker use or nonuse)
  • Dose increased if: SBP ≥90 mmHg (standing), absence of hypotension symptoms, serum creatinine ≤177 µmol/L or ≤1.5x of baseline serum creatinine. Follow-up at month 2, 4, 6 and then every 3 until completion of trial.
  • Baseline characteristics: 93% on ACE inhibitor, 35% on beta-blocker, 5% spironolactone
Results

Primary Endpoints

  • Mortality (all cause): 19.7% (valsartan) vs. 19.4% (placebo); RR 1.02 (0.88-1.18), p=0.80
  • Combined endpoint of mortality and morbidity: 28.8% (valsartan) vs. 32.1% (placebo); RR 0.87 (0.77-0.97), p=0.009. (morbidity defined as cardiac arrest with resuscitation, hospitalization for heart failure, IV inotropes or vasodilators)

Secondary Endpoints

  • Changes in LVEF from baseline: 4% (valsartan) vs. 3.2% (placebo), p=0.001
  • NYHA class: Improvement - 23.1% (valsartan) vs. 20.7% (placebo), p<0.001. Worsening - 10.1% (valsartan) vs. 12.8% (placebo), p<0.001
  • Quality of Life scores (Minnesota Living with Heart Failure questionnaire): little change in valsartan vs. worsened score by 1.9 in placebo (p=0.005)
  • Heart failure hospitalization was reduced by 27.5% with valsartan (p<0.001)
  • Subgroup analysis: Valsartan improved outcomes in all the predefined subgroups except in those receiving both beta-blocker and ACE inhibitor therapy - valsartan increased mortality (p=0.009) and showed a trend to increase the combined endpoint of mortality and morbidity (p=0.10)
Summary
In chronic heart failure patients receiving optimal pharmacologic therapy, the addition of valsartan significantly but modestly reduces the combined endpoint of mortality and morbidity, but not mortality alone. The addition of valsartan also improves the signs and symptoms of HF.