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

S ystolic H eart failure treatment with the If inhibitor ivabradine T rial. Michel Komajda and Karl Swedberg on behalf of the Investigators. Disclosures.

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

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  1. Systolic Heart failure treatment withthe Ifinhibitor ivabradine Trial Michel Komajda and Karl Swedberg on behalf of the Investigators

  2. Disclosures SHIFT Executive Committee members received fees, research grants, or both from Servier, as well as fees for speaking or consulting from other major cardiovascular pharmaceutical companies

  3. Background • Elevated heart rate is associated with poor outcome in a number of cardiovascular conditions including heart failure • Heart rate remains elevated in many heart failure patients despite treatment by beta-blockers • Ivabradine is a novel heart rate-lowering agent acting by inhibiting the If current in the sino-atrial node • We hypothesized that the addition of ivabradine to recommended therapy would be beneficial in heart failure patients with elevated heart rate

  4. Resting heart rate and mortality in HF post MI patients DIAMOND study; 1518 patients with HF post MI, 10 years follow up Mortality 1.0 > 91 bpm81-91 bpm71-80 bpm40-70 bpm 0.8 0.6 0.4 0.2 P<0.0001 0.0 0 2 4 6 8 10 Years Fosbol et al. Int J Cardiol, 2010;140:279-286.

  5. Ivabradine: pure heart rate reduction open closed closed RR Pure heart rate reduction 0 mV -40 mV -70 mV Ivabradine If inhibition reduces the diastolic depolarization slope, thereby lowering heart rate Thollon et al. Br J Pharmacol. 1994;112:37-42.

  6. Primary objective To evaluate whether the If inhibitor ivabradine improves cardiovascular outcomes in patients with 1. Moderate to severe chronic heart failure 2. Left ventricular ejection fraction 35% 3. Heart rate 70 bpm and 4. Recommended therapy

  7. Multinational study Bulgaria Czech Republic Estonia Hungary Europe Germany Portugal Belgium Greece Spain Denmark Ireland Sweden Finland Italy Turkey France The Netherlands UK Latvia Lithuania Norway Poland Romania Russia Slovakia Slovenia Ukraine North America Canada Asia China Hong Kong India South Korea Malaysia South America Argentina Brazil Chili Australia 6505 patients, 37 countries, 677 centres

  8. Inclusion criteria • 18 years • Class II to IV NYHA heart failure • Ischaemic/non-ischaemic aetiology • LV systolic dysfunction (EF 35%) • Heart rate 70 bpm • Sinus rhythm • Documented hospital admission for worsening heart failure 12 months Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

  9. 3.5 years Study design Ivabradine 7.5/5/2.5 mg bid according to Ivabradine 5 mg bid HR and tolerability Screening 7 to 30 days Matching placebo, bid Every 4 months D0 D14 D28 M4 Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

  10. Study endpoints Primary composite endpoint • Cardiovascular death • Hospitalisation for worsening heart failure Other endpoints • All-cause / CV / HF death • All-cause / CV / HF hospitalisation • Composite of CV death, hospitalisation for HF or non-fatal MI • NYHA class / Patient & Physician Global Assessment In total population and in patients with at least 50% target dose of beta-blockers Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81.

  11. Patients and follow-up 7411 screened 6558 randomized 3268 to ivabradine 3290 to placebo Excluded: 26 Excluded: 27 3241 analysed 2 lost to follow-up 3264 analysed 1 lost to follow-up Median study duration: 22.9 months; maximum: 41.7 months Swedberg K, et al. Lancet. 2010;online August 29.

  12. Baseline characteristics Swedberg K, et al. Lancet. 2010;online August 29.

  13. Baseline characteristics Swedberg K, et al. Lancet. 2010;online August 29.

  14. Ivabradine Placebo Chronic HF background treatment Patients (%) 100 91 91 90 89 90 84 83 80 70 61 59 60 50 40 30 22 22 20 10 4 3 0 Beta-blockers ACEIs and/or Diuretics Aldosterone Digitalis ICD/CRT ARBs antagonists Swedberg K, et al. Lancet. 2010;online August 29.

  15. Ivabradine 90 Placebo 80 70 60 50 40 30 20 10 0 Background beta-blocker treatment Patients (%) 100 89 89 56 56 26 26 At least 50% target daily dose Target daily dose BB at randomization Swedberg K, et al. Lancet. 2010;online August 29.

  16. Background beta-blocker treatment Swedberg K, et al. Lancet. 2010;online August 29.

  17. Mean heart rate reduction 70% of patients on ivabradine 7.5 mg bid Heart rate (bpm) 90 80 80 Placebo 75 75 70 67 Ivabradine 64 60 50 0 2 weeks 1 4 8 12 16 20 24 28 32 Months Swedberg K, et al. Lancet. 2010;online August 29.

  18. Primary composite endpoint(CV death or hospital admission for worsening HF) 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;online August 29.

  19. Hospitalization for HF Cumulative frequency (%) 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;online August 29.

  20. Cardiovascular death Cumulative frequency (%) 30 HR (95% CI), 0.91 (0.80–1.03), p=0.128 Placebo 20 Ivabradine 10 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;online August 29.

  21. Death from heart failure Cumulative frequency (%) 10 HR (95% CI), 0.74 (0.58–0.94), p=0.014 Placebo - 26% 5 Ivabradine 0 0 6 12 18 24 30 Months Swedberg K, et al. Lancet. 2010;online August 29.

  22. Effect of ivabradineon outcomes Swedberg K, et al. Lancet. 2010;online August 29.

  23. Effect of ivabradine in prespecified subgroups Test for interaction Age<65 years≥65 years SexMale Female Beta-blockersNo Yes Aetiology of heart failureNon-ischaemic Ischaemic NYHA classNYHA class II NYHA class III or IV DiabetesNo Yes HypertensionNo Yes Baseline heart rate<77 bpm ≥77 bpm p=0.029 0.5 1.0 1.5 Hazard ratio Favours ivabradine Favours placebo Swedberg K, et al. Lancet. 2010;online August 29.

  24. Ivabradine Placebo NYHA class changes Patients (%) 70 p=0.0003 68 70 60 50 40 28 30 24 20 10 6 5 0 Improvement Stability Worsening Swedberg K, et al. Lancet. 2010;online August 29.

  25. Ivabradine Placebo Patient Global Assessment 72 Improvement 68 21 Stability 25 7 p< 0.05 Worsening 8 0 10 20 30 40 50 60 70 80 Patients (%) last post randomisation value Swedberg K, et al. Lancet. 2010;online August 29.

  26. Ivabradine Placebo Physician Global Assessment 61 Improvement 57 31 Stability 34 8 p= 0.001 Worsening 9 0 10 20 30 40 50 60 70 Patients (%) last post randomisation value Swedberg K, et al. Lancet. 2010;online August 29.

  27. Mean heart rate reduction Patients with >50 % beta-blocker dose (n= 3181) Mean HR in sinus rhythm (bpm) 100 90 Placebo 79 74 80 75 70 67 60 63 Ivabradine 50 40 D14 D28 M04 M08 M12 M16 M20 M24 M28 M32 M36 Baseline Patients receiving at least half the target dose of beta-blockers Swedberg K, et al. Lancet. 2010;online August 29.

  28. Patients with at least 50% BB target dose (n=3181) p value Ivabradine Placebo Hazard ratio Primary compositeendpoint ns 330 (11.9 PY) 362 (13.3 PY) 0.90 ns Cardiovascular death 176 (5.9 PY) 175 (5.9 PY) 1.00 Hospital admission forworsening HF 213 (7.7 PY) 260 (9.6 PY) 0.81 p=0.021 0.5 1.0 1.5 Hazard ratio Favours ivabradine Favours placebo Swedberg K, et al. Lancet. 2010;online August 29.

  29. Incidence of selected adverse events (N = 6492) Swedberg K, et al. Lancet. 2010;online August 29.

  30. Incidence of serious adverse events 0.025 0.091 0.617 0.381 0.347 0.197 0.342 0.534 0.685 0.273 0.374 49%(1553) 30%(991) 8%(254) 7%(236) 4%(122) 4%(122) 3%(103) 2%(61) 1%(47) 1%(39) <1%(13) 45%(1450) 28%(920) 7%(240) 7%(216) 3%(107) 3%(102) 3%(89) 2%(68) 2%(51) 1%(29) 1%(18) Swedberg K, et al. Lancet. 2010;online August 29.

  31. Treatment discontinuation Swedberg K, et al. Lancet. 2010;online August 29.

  32. Conclusion • Heart failure with systolic dysfunction and elevated heart rate is associated with poor outcomes (primary composite endpoint in the placebo group is 18%/year) • Ivabradine reduced cardiovascular mortality or heart failure hospitalisation by 18% (p<0.0001). The absolute risk reduction was 4.2% • This beneficial effect was mainly driven by a favourable effect on HF death (26%) and hospitalisation for HF (26%) • Overall, treatment with ivabradine was safe and well tolerated

  33. Clinical implications • The addition of ivabradine to recommended therapy significantly reduces death and hospitalisations related to heart failure in patients with heart rate 70 bpm • The NNT for 1 year to prevent … • One primary endpoint is 26 • One hospitalisation for heart failure is 27

  34. Available now online from Lancet http://www.lancet.com published online August 29, 2010 DOI:10.1016/S0140-6736(10)61198-1

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