Optimization of Heart Failure Treatment by Heart Rate Reduction

Figure 1. Heart rate in the cardiovascular continuum and the potential influence of ivabradine. Heart rate is a risk indicator in all cardiovascular conditions but a modifiable risk factor only in chronic heart failure. Ivabradine binds to the HCN channel inhibiting If currents, thereby reducing the phase IV depolarization of the action potentials leading to heart rate reduction. Modified according to 11. HCN = hyperpolarization-activated cyclic nucleotide–gated.

Figure 2. Kaplan Meier cumulative event curves for the primary composite endpoint (cardiovascular death or heart failure hospitalization) according to patient groups defined by quintiles of heart rate at 28 days on placebo. Log rank p values show the difference between the groups. Modified according to 7.

Figure 3. Kaplan Meier cumulative event curves for the primary composite endpoint (cardiovascular death or heart failure hospitalization) for ivabradine or placebo. Primary results of the SHIFT study. Modified according to 10. HR = hazard ratio; SHIFT = Systolic Heart failure treatment with the If-inhibitor ivabradine Trial.

Figure 4. Forest plots (left) demonstrating the hazard ratio (with 95% CIs) for the primary composite endpoint (cardiovascular death or HF hospitalization), cardiovascular mortality, hospitalization for worsening of HF, death from HF, all-cause mortality, all-cause hospitalization and any cardiovascular hospitalization for ivabradine compared to placebo. On the right hand side, the annual incidents of the primary composite endpoint are given according to heart rate achieved after up-titration of ivabradine at 28 days or reduction of heart rate at 28 days. Please note that all endpoints were significantly reduced and this reduction is closely associated with heart rate achieved and heart rate reduction in patients with chronic HF at a heart rate ≥ 75 bpm. Modified according to 24. CI = confidence interval; HF= heart failure; HR = hazard ratio.

Figure 5. Outcomes according to comorbidities (comorbidities≥4) on the primary outcome (cardiovascular death or heart failure hospitalization) on ivabradine (left) or placebo (right). Data from the SHIFT study. Modified from 43. SHIFT = Systolic Heart failure treatment with the If-inhibitor ivabradine Trial.

Figure 6. Isometric force of contraction (left) and change in diastolic tension (right) in isolated electrically driven cardiac preparations in vitro from patients with severe heart failure (NYHA class IV) or NF. Please note that the heart failure force of contraction declined (negative force-frequency relationship, on negative “Treppe”) and relaxation deficit in NYHA class IV. Modified from 45. NF = non-failing hearts; NYHA = New York Heart Association.

Figure 7. Kaplan Meier cumulative event curves for the primary composite endpoint (cardiovascular death or heart failure hospitalization) according to patient groups defined by quintiles of heart rate achieved at 28 days on treatment with ivabradine. Log rank p-values show the difference between the groups. Modified according to 7.