A post-hoc analysis of the SHIFT trial was performed to explore whether ivabradine is beneficial in patients with systolic heart failure, in sinus rhythm, with resting heart rate = 70 b.p.m., and whose guideline-recommended background therapy includes a mineralocorticoid receptor antagonist (MRA). Methods and results The effect of ivabradine on the primary composite endpoint of cardiovascular death or hospitalization for worsening heart failure, and its components, was explored in 3922 SHIFT patients with MRAs at baseline vs. 2583 patients without. Patients with MRAs were younger and were more likely to have severe heart failure and less coronary artery disease or hypertension than those without these drugs. Event rates in the placebo group were higher in patients with MRAs (33 ) than in those without (23 ) for the primary composite endpoint, with a 40 increase in relative risk (hazard ratio 1.40, 95 confidence interval 1.22?1.61). This was also true for secondary endpoints related to mortality or hospitalization. The effect of ivabradine on reducing the primary endpoint was similar in patients with and without MRAs (P ? 0.916 for interaction, adjusted for prognostic factors at baseline), as were its effects on cardiovascular death (P ? 0.279), hospitalizations for heart failure (P ? 0.304), and death from heart failure and from all causes (P ? 0.723 and 0.366, respectively). There was no difference in the safety of ivabradine in the two subpopulations. Conclusion Ivabradine improves outcomes in heart failure patients with heart rate = 70 b.p.m. receiving multiple neurohormonal modulation treatments (angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, beta-blocker, and MRA). The addition of ivabradine to multiple neurohormonal modulation should therefore be considered when the heart rate is = 70 b.p.m.