Patients with one (n = 714), two (n = 254), and three or more (n = 218) hospitalizations for worsening HF during the study had more risk markers at the baseline (e.g. greater age, diabetes, renal dysfunction, and prior stroke) than those with no hospitalization for worsening HF (n = 5319; Table ). They were also more likely to have severe disease (e.g. 62–66% of hospitalized patients were in NYHA class III or IV vs. 49% for patients with no HF hospitalization during the study). Patients with one or more post-randomization HF hospitalization had higher resting heart rate, lower systolic and diastolic blood pressures, lower left ventricular ejection fraction, higher use of mineralocorticoid receptor antagonists and diuretics, and fewer prescriptions of β-blockers at randomization than those without a HF hospitalization after randomization. The baseline characteristics for SHIFT patients with at least one HF hospitalization during the study were generally similar in the placebo and ivabradine groups (Table ).
Baseline characteristics of patients according to the number of hospitalizations for worsening heart failure during the trial
Baseline characteristics of patients who were hospitalized at least once for worsening heart failure during the trial
In total, 1186 of the 6505 randomized patients experienced at least one HF hospitalization during the study. Of these 1186 patients, 472 suffered at least a second HF hospitalization and 218 experienced at least a third. Hospitalization for any cause occurred in 2587 patients after randomization, 1328 patients had at least two all-cause hospitalizations, and 718 patients had three or more.
When compared with the effect of placebo, ivabradine was associated with fewer total hospitalizations for worsening HF (902 events with ivabradine vs. 1211 events with placebo, IRR = 0.75, 95% CI, 0.65–0.87, P = 0.0002) during a median follow-up of 22.9 months (Figure ). Similar results for HF hospitalizations were seen in the higher risk subgroup of patients with a heart rate of ≥75 b.p.m. (n = 4150) (IRR = 0.73, 95% CI, 0.61–0.87, P = 0.0006). [The remaining group, with a heart rate 70–74 b.p.m., had directionally and qualitatively similar results to the ≥75 b.p.m. group; though the difference did not reach statistical significance in the lower heart rate group, there was no significant interaction (P = 0.069) for the groups with the lower and higher heart rates for the hospitalization outcome.]
Figure 1 Cumulative incidence of hospitalizations for worsening heart failure (mean number of events per patient) during the study. IRR, incidence rate ratio. CI, confidence interval. *Estimate of rate of hospitalizations over time (corrected for the competing (more ...)
Hospitalizations for any cause (2661 vs. 3110 events, IRR = 0.85, 95% CI, 0.78–0.94, P = 0.001) and cardiovascular hospitalizations (1909 vs. 2272 events, IRR = 0.84, 95% CI, 0.76–0.94, P = 0.002) were also less frequent with ivabradine than with placebo. Importantly, hospitalizations for causes other than worsening HF (1759 events with ivabradine vs. 1899 events with placebo, IRR = 0.92, 95% CI, 0.83–1.02, P = 0.12) were not increased by ivabradine. Hospitalizations (HF and all cause) are expressed per patient for all patients and for patients actually hospitalized in Table .
Hospitalizations expressed per patient for all patients and for patients actually hospitalized during the trial
Using the total time (cumulative) approach, over about 2 years of follow-up, ivabradine-treated patients were at significantly lower risk for suffering a second hospitalization for worsening HF than were patients receiving placebo (Figure ). The risk for suffering a third hospitalization for worsening HF was also significantly reduced by ivabradine (Figure ).
Figure 2 Estimate of treatment effect on recurrence of hospitalizations for worsening heart failure (total-time approach). The approach allows for a cumulative effect in which the second hospitalization includes the effect of the first, and the third hospitalization (more ...)
The gap-time approach analysis was performed in the patients with at least one hospitalization for worsening HF over a median follow-up of 21.1 months. The number of patients involved in this analysis provided only modest power to assess the effect and the result did not reach statistical significance (HR = 0.84, 95% CI, 0.69–1.01, P = 0.058), but the nominal effect on risk of second hospitalization for worsening HF with ivabradine compared with placebo was consistent with that found with the total-time approach. In addition, treatment with ivabradine was associated with more days alive out of hospital than with placebo (estimate, 13.00, 95% CI, 3.93–22.07, P = 0.005) during the study.