Effects of High- vs Low- dose ARBs on Outcomes in Patients with CHF

Abstract & Commentary

By Harold L. Karpman, MD, FACC, FACP, Clinical Professor of Medicine, UCLA School of Medicine. Dr. Karpman reports no financial relationship to this field of study.

Synopsis: Losartan 150 mg/day reduced left ventricular ejection fraction, intolerance to ACE inhibitors, and the rate of death and/or hospital admission for heart failure in patients with CHF more than did losartan 50 mg/day, thereby demonstrating the potential value of uptitrating ARB doses to confer clinical benefit.

Source: Konstam MA, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEALL study). Lancet 2009:374:1840-1848.

Multiple clinical trials have reported that angiotensin-receptor blockers (ARBs) administered with or without an angiotensin-converting enzyme (ACE) inhibitor effectively increase left ventricular ejection fraction (LVEF) and reduce morbidity and mortality in patients with heart failure (CHF).1-6 These trials were all performed testing the effects of a single dose of an ARB and therefore did not provide information regarding differences in the outcome effects of various dosing regimens. Incremental losartan doses of up to 150 mg in patients with CHF have demonstrated progressive increases in plasma renin activity and in circulating concentrations of angiotensin II,7 lending support to the possibility that higher ARB doses may improve clinical benefits through more complete inhibition of angiotensin effects at the angiotensin I receptor and/or increased stimulation of the angiotensin II receptor.8

Komstan et al performed the HEALL study, which compared clinical outcomes in patients with severe CHF (New York Heart Association class II-IV who were intolerant to ACE inhibitors and with an LVEF £ 40%) and who were randomly assigned either to a high (150 mg) or low (50 mg) daily dose of losartan. The primary endpoints were death and/or hospital admission for CHF. The double-blind trial was undertaken at 255 sites in 30 countries in 3846 patients with CHF. Patients receiving the 150 mg dose demonstrated superior outcomes compared to patients receiving the 50 mg dose with respect to the composite outcome of death and/or hospital admissions for CHF. More patients receiving the 150 mg dose had hyperkalemia, hypotension, and renal impairment than did the patients receiving the 50 mg dose; however, these adverse events only infrequently led to discontinuation of the assigned drug.

Commentary

The value of incremental inhibition of the renin-angiotensin system had been previously demonstrated by the results of the CHARM-Added trial,6 which revealed a 15% reduction in the rate of cardiovascular deaths or heart failure hospital admissions in patients treated with 32 mg of candesartan daily in a population already treated with ACE inhibitors. The HEALL study results suggest that a similar benefit can be achieved by increasing the dose of a particular agent rather than by adding another class of agents, although additional studies are obviously needed to directly test and solidify the hypothesis that titration of ARB doses to higher levels, unless limited by adverse effects such as hyperkalemia, hypo-tension, and/ or renal impairment, improves the clinical outcomes in patients with CHF with a reduced LVEF.

In summary, multiple published study results have clearly demonstrated that increased inhibition of the renin-angiotensin system is associated with extremely beneficial clinical results in patients with CHF. However, is not clear whether greater benefit might be achieved by adding an ACE inhibitor to an ARB compared with simply increasing the dose of an ARB, which is being administered without ACE inhibition. Further studies will clarify these issues, but for the time being, clinicians should consider adding an ARB to an ACE inhibitor or increasing the dose of an ARB in those patients with CHF who are not receiving ACE-inhibiting therapy and who are not doing well clinically.

References

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2. Pfeffer MA, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet 2003;362:759-766.

3. Pfeffer MA, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003;349:1893-1906.

4. Maggioni AP, et al. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002;40:1414-1421.

5. Krum H, et al. Effect of valsartan added to background ACE inhibitor therapy in patients with heart failure: Results from Val-HeFT. Eur J Heart 2004;6:937-945.

6. McMurray JJ, et al. Effects of candesartan in patients with chronic heart failure and reduced left ventricular systolic function taking angiotensin-converting-enzyme inhibitors. The CHARM-Added trial. Lancet 2003;362:767-771.

7. Gottlieb SS, et al. Hemodynamic and neurohormonal effects of the angiotensin II antagonist losartan in patients with congestive heart failure. Circulation 1993;88:1602-1609.

8. Dzau VJ, et al. Heterogeneity of angiotensin synthetic pathways and receptor subtypes: Physiological and pharmacological implications. J Hypertens Suppl 1993;11:S13-S18.