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S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial

S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial. Effect of i vabradine on recurrent hospitalization for worsening h eart failure: findings from SHIFT. Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22): 2813-2820. www.shift-study.com. Trial design.

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S ystolic H eart failure treatment with the I f inhibitor ivabradine T rial

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  1. Systolic Heart failure treatment withthe Ifinhibitor ivabradineTrial Effect of ivabradineon recurrent hospitalization for worsening heart failure: findings from SHIFT Borer JS, Böhm M, Ford I, et al. Eur Heart J. 2012;33(22):2813-2820 www.shift-study.com

  2. Trialdesign • Randomized, double-blind, placebo-controlled trial in 6505 patients to test the hypothesis that heart rate slowing with the Ifinhibitor 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 Swedberg K, et al. Lancet. 2010;376:875-885 www.shift-study.com

  3. Primary endpoint: composite of CVdeath or hospitalization for heartfailure Cumulative frequency (%) 40 HR(95% CI), 0.82 (0.75–0.90) P <0.0001 Placebo - 18% 30 Ivabradine 20 10 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;376:875-885 www.shift-study.com

  4. Secondary pre-specified endpoint: hospitalization for heart failure Hospitalization for HF (%) 30 Placebo • HR (95% CI), 0.74 (0.66;0.83) P <0.0001 - 26% 20 Ivabradine 10 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;376:875-885 www.shift-study.com

  5. Objective of the current analysis To assess the effect of heart rate slowing with ivabradineon recurrent hospitalizations for worsening heart failure Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  6. Rationale: HF hospitalization burden • 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. 2000 MedPAR data. DRG 127; Fonarow, GC. Rev Cardiovasc Med. 2002;3 (suppl 4):S3; Krumholz HM et al. R Arch Intern Med. 1997 Jan 13;157(1):99-104; Roger VL, Circulation. 2012;125(1):e2-e220. www.shift-study.com

  7. Economicburden of chronic HF Primary Care Post-dischargeoutpatientvisits Outpatientreferral Hospital admissions Drug treatment Hospitalizationaccounts for most CHF-associatedcosts Stewart S, et al. Eur J HeartFail. 2002;4:361-71 www.shift-study.com

  8. Analysis plan • Effect of ivabradineon • total hospitalizations: incidence rate ratio vs placebo • repeated hospitalizations: • total-time approach (time from randomization to 1st, 2nd and 3rdhospitalization) • gap-time approach (time from 1st to 2ndhospitalization) • All approaches adjusted for protocol-specified prognostic factors present pre-randomization (beta-blocker intake, NYHA class, ischaemic cause of HF, LVEF, age, SBP, HR, creatinineclearance) Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  9. Pre-randomization characteristics Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  10. Pre-randomization background treatment Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  11. Effect of ivabradine on total HF hospitalizations Cumulative incidence of HF hospitalizations (first and repeated) • IRR (95% CI), 0.75 (0.65;0.87) P=0.0002 40 • Placebo - 25% 30 • Ivabradine 20 10 0 0 6 12 18 24 30 Time (months) Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  12. Effect of ivabradine on recurrence of hospitalizations for HF Total-time approach Hazard ratio P-value Ivabradine (n=3241) Placebo (n=3264) First hospitalization 514 (16%) 672 (21%) P <0.001 0.75 Second hospitalization 189 (6%) P <0.001 283 (9%) 0.66 Third hospitalization 90 (3%) P<0.012 128 (4%) 0.71 1.0 0.4 0.6 0.8 1.2 Favours placebo Favoursivabradine Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  13. Recurrences of HF hospitalizationsGap-time approach = effect on 2nd hospitalisationTime from 1st hospitalization to 2nd hospitalisation Cumulativefrequency (%) HR (95% CI), 0.84 (0.69-1.01) P=0.058 Placebo 70 60 50 Ivabradine 40 30 20 10 0 0 6 24 12 Time from first hospitalization (months) 472 patients withat least a first and second hospitalisation for worsening HF Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  14. Total number of hospitalizations Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  15. 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. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

  16. Conclusion • Heart rate reduction with ivabradinein 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 Borer JS, Böhm M, Ford I, et al. EurHeart J. 2012;33(22):2813-2820 www.shift-study.com

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