Effect of ivabradine on recurrent hospitalization for worsening heart failure: findings from SHIFT S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22): www.shift-study.com

 Randomized, double-blind, placebo-controlled trial in 6505 patients to test the hypothesis that heart rate slowing with the I f inhibitor ivabradine improves cardiovascular outcomes in patients with: Moderate to severe chronic heart failure (HF) Hospitalization for worsening HF within the 12 months prior to randomization Left ventricular ejection fraction  35% Sinus rhythm and heart rate  70 bpm Receiving guidelines-based background HF therapy Trial design Swedberg K, et al. Lancet. 2010;376: www.shift-study.com

Months Primary endpoint: composite of CV death or hospitalization for heart failure - 18% Cumulative frequency (%) Placebo Ivabradine HR (95% CI), 0.82 (0.75–0.90) P < Swedberg K, et al. Lancet. 2010;376: www.shift-study.com

Months Secondary pre-specified endpoint: hospitalization for heart failure - 26% Hospitalization for HF (%) Placebo Ivabradine HR (95% CI), 0.74 (0.66;0.83) P < Swedberg K, et al. Lancet. 2010;376: www.shift-study.com

Objective of the current analysis To assess the effect of heart rate slowing with ivabradine on recurrent hospitalizations for worsening heart failure Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

 Predominant reason for hospital admissions in patients with HF = worsening HF  High readmission rate after initial hospitalization: 20% within one month 50% within six months 17% are readmitted two or more times  Hospitalization = the major contributor to the cost of HF care Centers for Medicare and Medicaid Services MedPAR data. DRG 127; Fonarow, GC. Rev Cardiovasc Med. 2002;3 (suppl 4):S3; Krumholz HM et al. R Arch Intern Med Jan 13;157(1):99-104; Roger VL, Circulation. 2012;125(1):e2-e220. Rationale: HF hospitalization burden

Economic burden of chronic HF Hospitalization accounts for most CHF-associated costs Stewart S, et al. Eur J Heart Fail. 2002;4: Primary Care Outpatient referral Drug treatment Post-discharge outpatient visits Hospital admissions

Analysis plan  Effect of ivabradine on total hospitalizations:total hospitalizations: incidence rate ratio vs placebo repeated hospitalizations: -total-time approach (time from randomization to 1 st, 2 nd and 3 rd hospitalization) hospitalization) -gap-time approach (time from 1 st to 2 nd hospitalization)  All approaches adjusted for protocol-specified prognostic factors present pre-randomization (beta-blocker intake, NYHA class, ischaemic cause of HF, LVEF, age, SBP, HR, creatinine clearance) Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

Pre-randomization characteristics Number of hospitalizations for HF during trial None (n=5319) One (n=714) Two (n=254) Three or > (n=218) P-value Age (years) < Male (%) Heart rate (bpm) < SBP (mmHg) < DBP (mmHg) < LVEF (%) < NYHA class II (%) < NYHA class III/IV (%) Duration of HF (years) < Diabetes (%) < Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

Pre-randomization background treatment Number of hospitalizations for HF during trial None (n=5319) One (n=714) Two (n=254) Three or > (n=218) P-value Beta-blockers (%) < ACEI and/or ARB (%) MRA (%) < Diuretics (%) < Digitalis (%) < Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

Placebo Ivabradine IRR (95% CI), 0.75 (0.65;0.87) P= Cumulative incidence of HF hospitalizations (first and repeated) Time (months) % Effect of ivabradine on total HF hospitalizations Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

Effect of ivabradine on recurrence of hospitalizations for HF Total-time approach Favours ivabradine Favours placebo First hospitalization Second hospitalization Third hospitalization Placebo (n=3264) Ivabradine (n=3241) Hazard ratio P-value P <0.001 P< (16%) 189 (6%) 90 (3%) 672 (21%) 283 (9%) 128 (4%) Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

Recurrences of HF hospitalizations Gap-time approach = effect on 2nd hospitalisation Time from 1st hospitalization to 2nd hospitalisation frequency (%) Cumulative frequency (%) Placebo Ivabradine HR (95% CI), 0.84 ( ) P= Time from first hospitalization (months) 472 patients with at least a first and second hospitalisation for worsening HF Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

Total number of hospitalizations Ivabradine (N=3241) Placebo (N=3264) IRR 95% CI p-value Hospitalization for worsening HF Hospitalization for any cause Cardiovascular hospitalisation Hospitalization for other than worsening of HF Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

Limitations  Both of the statistical models have well known limitations total-time approach: treatment effect dependent on previous hospitalizations (cumulative effect) gap-time approach: restricted set of patients; therefore, randomization not preserved  Data on hospitalization burden may be influenced by differences between health care systems in different countries Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):

 Heart rate reduction with ivabradine in patients with chronic HF, in sinus rhythm, with heart rate ≥70 bpm and already receiving guidelines-suggested therapies substantially decreases the risk of clinical deterioration as reflected by: reduction in the total hospitalizations for worsening HF reduction in the incidence of recurrent HF hospitalizations increase in time to first and subsequent hospitalizations  This benefit reduces the total burden of HF for the patient and can be expected to substantially reduce health care costs Conclusion Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):