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Ivabradine in Chronic Heart Failure

Adam DeVore, MD
Duke University Medical Center

Ivabradine in Chronic Heart Failure

  1. 1. Ivabradine in chronic heart failure Adam DeVore Duke Heart Failure Symposium October 15, 2016
  2. 2. Disclosures • Research grants to the Duke Clinical Research Institute from: American Heart Association, Amgen, Novartis • Consulting: Novartis
  3. 3. Heart Rate Reduction and All-Cause Mortality in Heart Failure Kjekshus J. Eur Heart J 1999.
  4. 4. Mechanism of Ivabradine Reduces heart rate independent of beta-blocker effect
  5. 5. Phase III RCT comparing heart rate reduction with ivabradine to placebo in patients with chronic, symptomatic HFrEF (LVEF < 35%) and elevated heart rate (>70bpm)
  6. 6. www.shift-study.com  18 years  Class II to IV NYHA heart failure  Ischemic/non-ischemic etiology  LV systolic dysfunction (EF 35%)  Heart rate 70 bpm  Sinus rhythm  Documented hospital admission for worsening heart failure 12 months Inclusion criteria Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81
  7. 7. www.shift-study.com Study design HR and tolerability Ivabradine 5 mg bid Matching placebo, bid Every 4 monthsD0 D14 D28 M4 Ivabradine 7.5/5/2.5 mg bid according to Swedberg K, et al. Eur J Heart Fail. 2010;12:75-81. 3.5 years Screening 7 to 30 days
  8. 8. www.shift-study.com Mean heart rate reduction Mean ivabradine dose: - 6.4 mg bid at 1 month and 6.5 mg bid at 1 year 0 2 weeks 1 4 8 12 16 20 24 28 32 Months 90 80 70 60 50 67 75 75 80 64 Ivabradine Placebo Heart rate (bpm)
  9. 9. www.shift-study.com 0 6 12 18 24 30 40 30 20 10 0 Primary composite endpoint (CV death or hospital admission for worsening HF) 18% Cumulative frequency (%) Placebo Ivabradine HR = 0.82 (0.75–0.90) P < 0.0001 Months Swedberg K, et al. Lancet. 2010;376(9744):875-885
  10. 10. Effect of ivabradine on outcomes Endpoints Hazard ratio 95% CI p value Primary composite endpoint (CV death or hospital admission for worsening HF) 0.82 [0.75;0.90] p<0.0001 All-cause mortality 0.90 [0.80;1.02] p=0.092 Death from heart failure 0.74 [0.58;0.94] p=0.014 All-cause hospital admission 0.89 [0.82;0.96] p=0.003 Any CV hospital admission 0.85 [0.78;0.92] p=0.0002 CV death/hospital admission for HF or non-fatal MI 0.82 [0.74;0.89] p<0.0001 www.shift-study.comSwedberg K, et al. Lancet. 2010;376(9744):875-885
  11. 11. 2016 ACC/AHA/HFSA Heart Failure Update 2012 European HF Guidelines Yancy CW, et al. JACC 2016 McMurray JJV, et al. EHJ 2012 Recommendation for Ivabradine COR LOE Recommendation IIa B-R Ivabradine can be beneficial to reduce HF hospitalization for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF< 35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of 70 bpm or greater at rest (37-40). Ivabradine Guideline Recommendations
  12. 12. Ivabradine: Questions and Caveats • Can these clinical benefits be achieved with more aggressive use of beta-blockers? • What proportion of appropriately treated HF patients would qualify? • How do we interpret the results given the lack of US patients and no African-Americans? • What about concerning results of other studies? – BEAUTIFUL: No overall improvement in stable CAD but decreased risk of coronary events – SIGNIFY: No improvement in stable CAD with HR > 70, suggestion of increased risk in patients with significant angina Fox et al, Lancet, 2008 Fox, et al NEJM 2014
  13. 13. www.shift-study.com 0 10 20 30 40 50 60 70 80 90 100 BB at randomization At least 50% target daily dose Target daily dose 89 56 26 89 56 26 Patients (%) Background beta-blocker use Swedberg K, et al. Lancet. 2010;376(9744):875-885 Ivabradine Placebo
  14. 14. Discharge HR in OPTIMIZE-HF Registry Stratified by Target Beta-blocker Dose DeVore et al. Am Heart J. 2016 Mar;173:172-8 Beta-blocker use: • None: 28% • <25% target: 26% • 25-49% target: 25% • >50% target : 22% Of patients on >50% target dose, 65% had a resting heart rate of >70 bpm at discharge
  15. 15. It takes an average of 17 years for new knowledge generated by randomized controlled trails to be incorporated into practice, and even then application is highly uneven Applying Evidence to Health Care Delivery
  16. 16. PRIME-HF PredischaRge Initiation of Ivabradine in the Management of Heart Failure • 450 patient strategy trial – 50 US sites • Initiating ivabradine during a hospitalization for acute heart failure – After stabilization and prior to discharge • Compared to usual care – Consideration of starting as an outpatient
  17. 17. PRIME-HF • Primary Endpoint: Uptake of ivabradine at 180 days post- discharge • Secondary: QOL, HR, beta-blocker use and dose • Ancillary Study – wearable technology
  18. 18. In the IMPACT-HF study, predischarge initiation of carvedilol improved the use of beta-blockers at 60 days without increasing side effects or length of stay compared to usual care
  19. 19. Conclusions • The SHIFT study demonstrated that heart rate reduction with ivabradine improved clinical outcomes for patients with chronic, symptomatic HFrEF and elevated heart rate compared to placebo • Ivabradine is recommended to reduce HF hospitalizations for patients with symptomatic (NYHA class II-III) stable chronic HFrEF (LVEF <35%) who are receiving GDEM, including a beta blocker at maximum tolerated dose, and who are in sinus rhythm with a heart rate of >70 bpm at rest

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