• Clinical trials in patients with HF show b-blockers reduce mortality and improve outcomes. Because not all patients reached the maximum dose, clinicians have questioned whether maximum doses are necessary to benefit from treatment. In a post hoc analysis of MERIT-HF, Wikstrand et al¹ investigated heart rate during titration phase in two dosage groups. This analysis produced additional information on this issue.

• The high-dose subgroup (n = 1202) reached >100 mg of ER metoprolol succinate once daily (mean dose 192 mg).

• The low-dose subgroup (n = 412) reached <100 mg once daily (mean dose 76 mg).

• Starting from a similar heart rate of 81 and 83 beats/min (high- vs low-dose, respectively), both groups reached a heart rate of 67 beats/min. This indicates that the low-dose group had a higher sensitivity for b-blockade. For each milligram of b-blocker, heart rate was reduced 0.21 beats/min in the low-dose group versus 0.08 beats/min in the high-dose group.

• This observation is important to understanding the clinical benefits of treatment in the two subgroups. Greater sensitivity to b-blockade in the low-dose group might be caused by downregulation and densensitization of myocardial b₁-receptors in patients with more advanced disease,² which predominated in the low-dose subgroup. The low-dose group had more patients in class III and IV HF.

• Clinical outcomes in the high- and low-dose groups are discussed on the next slide.

¹Wikstrand J, Hjalmarson A, Waagstein F, Fagerberg B, Goldstein S, Kjekshus J, Wedel H. Dose of metoprolol CR/XL and clinical outcomes in patients with heart failure: Analysis of the experience in Metoprolol CR/XL Randomized Intervention Trial in Heart Failure (MERIT-HF). J Am Coll Cardiol. 2002;40:491-498.

²Bristow MR, Ginsburg R, Mintobe W, Cubicciotti RS, Sageman WS, Lurie K, et al. Decreased catecholamine sensitivity and beta-adrenergic-receptor density in failing human hearts. N Engl J Med. 1982;307:205-211.